Novel compounds

ABSTRACT

Novel substituted 1,5,7-trisubstituted-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-(1H)-one compounds and compositions, and their use in therapy as CSBP/RK/p38 kinase inhibitors.

RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 11/389,112, filed 24Mar. 2006 (now allowed) which claims the benefit of priority fromprovisional application U.S. Ser. No. 60/665,347, filed 25 Mar. 2005.

SUMMARY OF THE INVENTION

This invention relates to novel1,5,7-trisubstituted-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-[1H]-onecompounds and their use as pharmaceuticals, particularly as p38 kinaseinhibitors, for the treatment of certain diseases and conditions.

BACKGROUND OF THE INVENTION

Intracellular signal transduction is the means by which cells respond toextracellular stimuli. Regardless of the nature of the cell surfacereceptor (e. g. protein tyrosine kinase or seven-transmembrane G-proteincoupled), protein kinases and phosphatases along with phospholipases arethe essential machinery by which the signal is further transmittedwithin the cell [Marshall, J. C. Cell, 80, 179-278 (1995)]. Proteinkinases can be categorized into five classes with the two major classesbeing tyrosine kinases and serine/threonine kinases, depending uponwhether the enzyme phosphorylates its substrate(s) on specifictyrosine(s) or serine/threonine(s) residues [Hunter, T., Methods inEnzymology (Protein Kinase Classification) p. 3, Hunter, T.; Sefton, B.M.; eds. vol. 200, Academic Press; San Diego, 1991].

Three major related intracellular pathways, the mitogen-activatedkinases, or MAPKs, are now understood to transduce signals from manyextracellular stimuli such as environmental stress, infectious agents,cytokines and growth factors. The MAPKs modulate the activity ofnumerous cell functions such as translocation and activation oftranscription factors that control transcription of effector moleculessuch as cytokines, COX-2, iNOS; the activity of downstream kinases thateffect translation of mRNAs; and cell cycle pathways throughtranscription or modification of enzymes. One of these three majorpathways is the p38 MAPK pathway, which refers in most cell types to theisoform p38a which is ubiquitously expressed. The role of p38 in amultitude of functions, particularly related to inflammatory responsehas been elucidated using selective p38 inhibitors in numerous in vitroand in vivo studies. These functions have been extensively reviewed anda summary can be found in Nature Reviews [Kumar, S. Nature Rev. DrugDiscovery, 2:717 (2003)]

Extracellular stimuli such as those described above are generated in anumber of chronic diseases which are now understood to have a commonunderlying pathophysiology termed inflammation. An environmental insultor local cell damage activates cellular response pathways, including butnot limited to p38; local cells then generate cytokines and chemokines,in turn recruiting lymphocytes such as neutrophils and othergranulocytes. In a secondary response, the consequences includerecruitment of additional lymphocytes such as additional phagocyticcells or cytotoxic T cells, and ultimately the adaptive immune responseis initiated through activation of T cells. It is not currently fullyunderstood how this acute inflammatory response becomes a chronicresponse leading to diseases such as rheumatoid arthritis (RA),athersclerosis, chronic obstructive pulmonary disease (COPD),inflammatory bowel disease (IBD), etc. Nevertheless, the features ofinflammation are recognized to contribute to a large number of chronicdiseases and pathways such as the p38 pathway are accepted to contributeto the initiation of inflammatory diseases.

For example, atherosclerosis is regarded as a chronic inflammatorydisease, which develops in response to injury of the vessel wall and ischaracterized by the complex development of an occlusive andprothrombotic atheroma. The pathogenesis of this lesion generallyinvolves endothelial dysfunction (reduced bioavailable NO), adhesionmolecule expression, adhesion and infiltration of leukocytes, cytokineand growth factor generation, accumulation of foam cells, expansion ofextracellular lipid and matrix, activation of matrix metalloproteases(MMPs) and proliferation of vascular smooth muscle cells.

The discovery of p38 (initially termed CSBP, now p38; the isoforms p38αand p38β are the targets of the compounds described) provided amechanism of action of a class of anti-inflammatory compounds for whichSK&F 86002 was the prototypic example. These compounds inhibited IL-1and TNF synthesis in human monocytes at concentrations in the low uMrange [Lee, et al., Int. J. Immunopharmac. 10(7), 835(1988)] andexhibited activity in animal models which are refractory tocyclooxygenase inhibitors [Lee; et al., Annals N.Y. Acad. Sci., 696,149(1993)].

The mechanism by which stress signals (including bacterial and viralinfection, pro-inflammatory cytokines, oxidants, UV light and osmoticstress) activate p38 is through activation of kinases upstream from p38which in turn phosphorylate p38 at threonine 180 and tyrosine 182resulting in p38 activation. MAPKAP kinase-2 and MAPKAP kinase-3 havebeen identified as downstream substrates of CSBP/p38 which in turnphosphorylate heat shock protein Hsp27 and other substrates. Additionaldownstream substrates known to be phosphorylated by p38 include kinases(Mnk1/2, MSK1/2 and PRAK) and transcription factors (CHOP, MEF2, ATF2and CREB). While many of the signaling pathways required fortransduction of stress stimuli remain unknown it appears clear that manyof the substrates for p38 listed above are involved. [Cohen, P. TrendsCell Biol., 353-361(1997) and Lee, J. C. et al, Pharmacol. Ther. vol.82, nos. 2-3, pp. 389-397, 1999]. There is also emerging evidence thatp38 is involved in modulation of the activity of the NF-kB signalingpathway through a role in histone phosphorylation or acetylation, orthrough reduction of transcription competence of the NF-kB complex[Saccini, S. Nature Immunol., 3: 69-75, (2002); Carter, A B et al J BiolChem 274: 30858-63 (1999)]. Finally, a role for p38 in generation ofresponse to IFNs through activation by the Type I IFN receptor has beendescribed [Platanias, Pharmacol. Therap. 98:129-142 (2003)]. Activationof p38 is involved in the transcriptional regulation of IFN sensitivegenes through modification of specific transcription factors binding topromotor elements in these genes. Direct phosphorylation of STATs by p38has not been conclusively demonstrated.

In addition to inhibiting IL-1 and TNF upregulation in response toinflammatory stimuli, p38 kinase inhibitors (e.g., SK&F 86002 andSB-203580) are effective in a number of different cell types indecreasing the synthesis of a wide variety of pro-inflammatory proteinsincluding, IL-6, IL-8, GM-CSF, RANTES and COX-2. Inhibitors of p38kinase have also been shown to suppress the TNF-induced expression ofVCAM-1 on endothelial cells, the TNF-induced phosphorylation andactivation of cytosolic PLA2 and the IL-1-stimulated synthesis ofcollagenase and stromelysin. These and additional data demonstrate thatp38 is involved not only cytokine synthesis in response to stress, butalso in propagating the consequent cytokine signaling [CSBP/P38 kinasereviewed in Cohen, P. Trends Cell Biol., 353-361(1997)].

Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are importantinflammatory cytokines produced by a variety of cells, such asmonocytes, macrophages, and smooth muscle cells. IL-1 has beendemonstrated to mediate a variety of biological activities thought to beimportant in immunoregulation and other physiological conditions such asinflammation [See, e.g., Dinarello et al., Rev. Infect. Disease, 6, 51(1984)]. The myriad of known biological activities of IL-1 include theactivation of T helper cells, induction of fever, stimulation ofprostaglandin or collagenase production, neutrophil chemotaxis,induction of acute phase proteins and the suppression of plasma ironlevels.

There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease.These include rheumatoid arthritis, osteoarthritis, endotoxemia and/ortoxic shock syndrome, other acute or chronic inflammatory disease statessuch as the inflammatory reaction induced by endotoxin or inflammatorybowel disease; tuberculosis, atherosclerosis, muscle degeneration,cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis,gout, traumatic arthritis, rubella arthritis, and acute synovitis.Evidence also links IL-1 activity to diabetes and pancreatic β cells[review of the biological activities which have been attributed to IL-1Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985)].

Excessive or unregulated TNF production has been implicated in mediatingor exacerbating a number of diseases including rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions; sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, cerebral malaria, chronic obstructive pulmonary disease,silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusioninjury, graft vs. host reaction, allograft rejections, fever andmyalgias due to infection, such as influenza, cachexia secondary toinfection or malignancy, cachexia, secondary to acquired immunedeficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloidformation, scar tissue formation, Crohn's disease, ulcerative colitis,or pyresis.

Inflammatory diseases are also marked by increases in IL-6 andC-reactive protein (CRP), both of which are sensitive to inhibition byp38 inhibitors. IL-6 stimulation of CRP production is directly inhibitedby p38 inhibitors in human vascular endothelial cells, and CRP isproduced by hepatocytes in response to IL-6. CRP is considered a majorrisk factor for cardiovascular disease [Circulation 2003.107: 363-369]and may be a significant independent risk factor for chronic obstructivepulmonary disease [Circulation 2003. 107:1514-1519]. IL-6 is alsoupregulated in endometriosis [Bedaiwy et al., 2002, Human Reproduction17:426-431; Witz, 2000, Fertility and Sterility 73: 212-214].

Interleukin-8 (IL-8) and RANTES are chemotactic factors produced byseveral cell types including mononuclear cells, fibroblasts, endothelialcells, epithelial cells, neutrophils and T cells. Chemokine productionis induced by pro-inflammatory stimuli such as IL-1, TNF, orlipopolysachharide (LPS), or viral infection. IL-8 stimulates a numberof functions in vitro. It has been shown to have chemoattractantproperties for neutrophils, T-lymphocytes, and basophils. In addition itinduces histamine release from basophils from both normal and atopicindividuals as well as lysozomal enzyme release and respiratory burstfrom neutrophils. IL-8 has also been shown to increase the surfaceexpression of Mac-1 (CD11b/CD18) on neutrophils without de novo proteinsynthesis, which may contribute to increased adhesion of the neutrophilsto vascular endothelial cells. Many diseases are characterized bymassive neutrophil infiltration. Conditions such as chronic obstructivepulmonary disease associated with an increase in IL-8 production wouldbenefit by compounds which are suppressive of IL-8 production. RANTES isproduced by cells such as epithelial cells and airway smooth muscle inresponse to infection or cytokine stimulation. Its main chemoattractionis for T cell subtypes and blood-borne monocytes.

IL-1, TNF and other cytokines affect a wide variety of cells and tissuesand these cytokines as well as other leukocyte derived cytokines areimportant as critical inflammatory mediators of a wide variety ofdisease states and conditions. The inhibition of these cytokines is ofbenefit in controlling, reducing and alleviating many of these diseasestates.

In addition to the involvement of p38 signaling in the production ofIL-1, TNF, IL-8, IL-6, GM-CSF, COX-2, collagenase and stromelysin,signal transduction via CSBP/p38 is required for the effector functionsof several of these same pro-inflammatory proteins plus many others. Forexample, growth factors such as VEGF, PDGF, NGF signal through surfacereceptors which in turn activate cellular signaling pathways includingp38 MAPK [Ono, K. and Han, J., Cellular Signalling, 12 1-13 (2000);Kyriakis, J M and Avruch, J. Physiol Rev 81: 807-869 (2001)]. TGF_(χ), akey molecule in the control of inflammatory response, also activates p38as a consequence of engagement of the TGFβ receptor. The involvement ofCSBP/p38 in multiple stress-induced signal transduction pathwaysprovides additional rationale for the potential utility of CSBP/p38 inthe treatment of diseases resulting from the excessive and destructiveactivation of the immune system, or chronic inflammation. Thisexpectation is supported by the potent and diverse activities describedfor CSBP/p38 kinase inhibitors [Badger, et al., J. Pharm. Exp. Thera.279 (3): 1453-1461.(1996); Griswold, et al, Pharmacol. Comm. 7, 323-229(1996); Jackson, et al., J. Pharmacol. Exp. Ther. 284, 687-692 (1998);Underwood, et al., J. Pharmacol. Exp. Ther. 293, 281-288 (2000); Badger,et al., Arthritis Rheum. 43, 175-183 (2000)].

Chronic inflammation is also characterized by ongoing remodeling andrepair of affected tissue, leading in some cases to excess fibrotictissue. A role for p38 MAPK in fibrosis is supported by findings thatthis enzyme mediates signaling of transforming growth factor beta(TGF-β) on markers and proteins of fibrosis. For example, it has beenshown that TGF-β increases the kinase activity of p38 MAPK through theTGF-β activated kinase TAK-1 (Hanafusa et al., 1999, J. Biol. Chem.274:27161-27167). Furthermore, the p38 inhibitor SB-242235 inhibited theTGF-β-induced increases in fibronectin and thrombospondin (Laping etal., 2002, Molec. Pharmacol. 62:58-64). These results show that p38 MAPKis a key signaling intermediate for the effect of the pro-fibroticcytokine TGF-β on components of the extracellular matrix and markers offibrosis.

P38 also plays a role in directing survival and apoptosis of cells inresponse to various stimuli. Both survival and apoptosis can be p38regulated depending on the stimulus and the cell type [Morin and Huot,Cancer Research. 64:1893-1898 (2004)]. For example, TGF-beta canstimulate apoptosis in murine hepatocytes through activation of gadd45b,a protein involved in cell-cycle control, in a p38 mediated process [Yooet al, J. Biol. Chem. 278:43001-43007, (2003)]. In a different responsepathway, UV-stress can activate p38 and trigger apoptosis of a damagedcell. P38 has also been shown to promote survival of lymphocytes inresponse to stress, including neutrophils and CD8+ T cells.

There remains a need for treatment, in this field, for compounds whichare cytokine suppressive anti-inflammatory drugs, i.e. compounds whichare capable of inhibiting the CSBP/p38/RK kinase. The present inventionis directed to such novel compounds which are inhibitors of p38 kinase.

SUMMARY OF THE INVENTION

This invention relates to the novel compounds of Formula (I) and (Ia),(II) and (IIa), (III) and (IIIa), (IV) and (IVa), (V) and (Va), (VI),(VIa-VIi), (VIII) and (VIIIa), (IX) and (IXa), (A), (A1), (B), and (B1),and a pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof; and pharmaceutical compositionscomprising a compound of Formula (I) and (Ia), (II) and (IIa), (III) and(IIIa), (IV) and (IVa), (V) and (Va), (VI), (VIa-VIi), (VIII) and(VIIIa), (IX) and (IXa), (A), (A1), (B), and (B1), and apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof, in admixture with a pharmaceutically acceptablediluent or carrier.

This invention relates to a method of treating a CSBP/RK/p38 kinasemediated disease in a mammal in need thereof, which comprisesadministering to said mammal an effective amount of a compound ofFormula (I) and (Ia), (II) and (IIa), (III) and (IIIa), (IV) and (IVa),(V) and (Va), (VI), (VIa-VIi), (VIII) and (VIIIa), (IX) and (IXa), (A),(A1), (B), and (B1), and a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof.

This invention also relates to a method of inhibiting cytokines and thetreatment of a cytokine mediated disease, in a mammal in need thereof,which comprises administering to said mammal an effective amount of acompound of Formula (I) and (Ia), (II) and (IIa), (III) and (IIIa), (IV)and (IVa), (V) and (Va), (VI), (VIa-VIi), (VIII) and (VIIIa), (IX) and(IXa), (A), (A1), (B), and (B1), and a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof.

This invention also relates to a method of inhibiting the production ofIL-1 in a mammal in need thereof which comprises administering to saidmammal an effective amount of a compound of Formula (I) and (Ia), (II)and (IIa), (III) and (IIIa), (IV) and (IVa), (V) and (Va), (VI),(VIa-VIi), (VIII) and (VIIIa), (IX) and (IXa), (A), (A1), (B), and (B1),and a pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof.

This invention also relates to a method of inhibiting the production ofIL-6 in a mammal in need thereof which comprises administering to saidmammal an effective amount of a compound of Formula (I) and (Ia), (II)and (IIa), (III) and (IIIa), (IV) and (IVa), (V) and (Va), (VI),(VIa-VIi), (VIII) and (VIIIa), (IX) and (IXa), (A), (A1), (B), and (B1),and a pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof.

This invention also relates to a method of inhibiting the production ofIL-8 in a mammal in need thereof which comprises administering to saidmammal an effective amount of a compound of Formula (I) and (Ia), (II)and (IIa), (III) and (IIIa), (IV) and (IVa), (V) and (Va), (VI),(VIa-VIi), (VIII) and (VIIIa), (IX) and (IXa), (A), (A1), (B), and (B1),and a pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof.

This invention also relates to a method of inhibiting the production ofTNF in a mammal in need thereof which comprises administering to saidmammal an effective amount of a compound of Formula (I) and (Ia), (II)and (IIa), (III) and (IIIa), (IV) and (IVa), (V) and (Va), (VI),(VIa-VIi), (VIII) and (VIIIa), (IX) and (IXa), (A), (A1), (B), and (B1),and a pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof.

Accordingly, the present invention provides for a compound of Formula(I) and (Ia) having the structure:

wherein

-   G₁, and G₂ are independently nitrogen;-   G₃ is NH;-   G₄ is nitrogen;-   R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b,)    N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);    N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); or    N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b);-   R_(1′) is independently selected at each occurence from halogen,    C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,    (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅,    S(O)₂R_(5,) or (CR₁₀R₂₀)_(v′)OR₁₃;-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or heterocyclylC₁₋₁₀ alkyl    moiety, which moieties excluding hydrogen, may all be optionally    substituted;-   X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′), (CH₂)_(n′)N(R_(10′))C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or    -   R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    -   (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein each of these moieties, excluding hydrogen, may be    optionally substituted;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein these moieties, excluding hydrogen, may be optionally    substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀ alkyl, or a heterocyclylC₁₋₁₀    alkyl moiety, and wherein each of these moieties may be optionally    substituted;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, and wherein each of    these moieties, excluding hydrogen, may be optionally substituted;    or the R₄ and R₁₄ together with the nitrogen which they are attached    form an optionally substituted heterocyclic ring of 4 to 7 members,    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or nitrogen;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′)    together with the nitrogen to which they are attached form a    heterocyclic ring of 5 to 7 members, which ring optionally contains    an additional heteroatom selected from NR_(9′);-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′,) S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R₁₀′ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R_(d) and R_(d′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylC₁₋₄alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted; or R_(d) and R_(d′) together with the    nitrogen which they are attached form an optionally substituted    heterocyclic ring of 5 to 6 members, which ring optionally contains    an additional heteroatom selected from oxygen, sulfur or NR_(9′);-   g is 0 or an integer having a value of 1, 2, 3, or 4;-   n′ is independently selected at each occurrence from 0 or an integer    having a value of 1 to 10;-   m is independently selected at each occurrence from 0 or an integer    having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6;-   t is an integer having a value of 2 to 6;-   v is 0 or an integer having a value of 1 or 2;-   v′ is independently selected at each occurrence from 0 or an integer    having a value of 1 or 2;-   Z is independently selected at each occurrence from oxygen or    sulfur; or-   a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

DETAILED DESCRIPTION OF THE INVENTION

The novel compound of Formula (I) are discussed in greater detaildescribed below.

The present invention is directed to novel compounds of Formula (I) and(Ia), (II) and (IIa), (III) and (IIIa), (IV) and (IVa), (V) and (Va),(VI) and (VIa-VIi), (A), (A1), (B), (B1), (VI), (VIa), (VIII) and(VIIIa), (IX) and (IXa), or a pharmaceutically acceptable salt, solvateor physiologically functional derivative thereof. As will be readilyrecognized, the difference between compounds of Formula (I) and (Ia)lies in unsaturation of the ring system. The difference between compoundof Formula (I) and (Ia) and compounds of Formula (II) and (IIa), (III)and (IIIa), (IV) and (IVa), (V) and (Va), (VI) and (VIa-VIi), (A), (A1),(B), (B1), (VI), (VIa), (VIII) and (VIIIa) lies in ring substitution ofthe R₁ substituent on the aryl (or heteroaryl moiety when G5 and/or G6,etc are nitrogen), and the ring position of the nitrogen(s) for thepyridyl or pyrimidine pharmacophore where applicable. It is recognizedthat the ring position numbering may change due to the nitrogen's in thepharmacophore ring and or in the ring that the R1 substituent isattached in.

The respective R₁, R_(1′), R₂, R₃, R_(X), X and R₃, etc., terms are thesame for both groups within the formulas themselves, for instance, inFormula (I) and (Ia), and except for the additional G5/G6/G7/G8 terms,applicable across all formulas herein. For purposes herein, everythingapplicable to Formula (I) is also applicable to Formula (Ia) unlessotherwise indicated, and for the remaining compounds of Formula (II) and(IIa), etc. unless specified otherwise.

It is recognized that for compounds of Formula (I) and (Ia) wherein G₃and G₄ are both nitrogen and G₁ and G₂ are both nitrogen, the ringsystem is considered to be a1,5,7-trisubstituted-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-[1H]-one.

Compounds of Formula (I) and (Ia) are further represented by thestructure:

wherein

-   G₁, and G₂ are independently nitrogen;-   G₃ is NH;-   G₄ is nitrogen;-   R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b,)    N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);    N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); or    N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b);-   R_(1′) is independently selected at each occurrence from hydrogen,    halogen, C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,    (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅,    S(O)₂R_(5,) or (CR₁₀R₂₀)_(v′)OR₁₃;-   X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′), (CH₂)_(n′)N(R_(10′))C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2′))(R_(2″)), or N(R_(10′))R_(h)    NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted; or R_(q) and R_(q′)    together with the nitrogen to which they are attached form an    optionally substituted heterocyclic ring of 5 to 7 members, which    ring may contain an additional heteroatom selected from oxygen,    nitrogen or sulfur;-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally C₁₋₁₀ alkyl;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    -   wherein these moieties, excluding hydrogen, may be optionally        substituted 1 to 4 times, independently at each occurrence from        C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀        alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,        C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenyl C₁₋₁₀ alkyl, halogen, —C(O),        cyano, nitro, aryl, aryl C₁₋₁₀ alkyl, heteroaryl,        heteroarylC₁₋₁₀ alkyl, heterocyclic, heterocyclylC₁₋₁₀ alkyl,        (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇,        (CR₁₀R₂₀)_(n)N(R_(10′))S(O)₂R₇, (CR₁₀R₂₀)_(n)NR_(e)R_(e′),        (CR₁₀R₂₀)_(n)NR_(e)R_(e′)C₁₋₄alkyl NR_(e)R_(e′),        (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR_(e)R_(e′),        (CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,        (CR₁₀R₂₀)_(n)C(Z)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆,        (CR₁₀R₂₀)_(n)N(R_(10′))C(═N(R_(10′)))NR_(e)R_(e′),        (CR₁₀R₂₀)_(n)C(═NOR₆)NR_(e)R_(e′),        (CR₁₀R₂₀)_(n)OC(Z)NR_(e)R_(e′),        (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR_(e)R_(e′), or        (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇; or wherein R₂ is the moiety        (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or        (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    -   wherein each of these moieties, excluding hydrogen, may be        optionally substituted 1 to 4 times, independently at each        occurrence from C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl,        C₃₋₇cycloalkylC₁₋₁₀alkyl, C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenyl        C₁₋₁₀ alkyl, halogen, —C(O), cyano, nitro, aryl, aryl C₁₋₁₀        alkyl, heterocyclic, heterocyclic C₁₋₁₀ alkyl, heteroaryl,        heteroaryl C₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH,        (CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)N(R_(10′)′)S(O)₂R₇,        (CR₁₀R₂₀)_(n)NR_(e)R_(e′),        (CR₁₀R₂₀)_(n)NR_(e)R_(e′)C₁₋₄alkylNR_(e)R_(e′), (CR₁₀R₂₀)_(n)CN,        (CR₁₀R₂₀)_(n)S(O)₂NR_(e)R_(e′), (CR₁₀R₂₀)_(n)C(Z)R₆,        (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,        (CR₁₀R₂₀)_(n)C(Z)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆,        (CR₁₀R₂₀)_(n)N(R10′)C(═N(R_(10′)))NR_(e)R_(e′),        (CR₁₀R₂₀)_(n)C(═NOR₆)NR_(e)R_(e′),        (CR₁₀R₂₀)_(n)OC(Z)NR_(e)R_(e′),        (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR_(e)R_(e′), or        (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    -   wherein these moieties, excluding hydrogen, may be optionally        substituted 1 to 4 times, independently at each occurrence from        C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀        alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,        C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenyl C₁₋₁₀ alkyl, halogen, —C(O),        cyano, nitro, aryl, aryl C₁₋₁₀ alkyl, heteroaryl,        heteroarylC₁₋₁₀ alkyl, heterocyclic, heterocyclylC₁₋₁₀ alkyl,        (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇,        (CR₁₀R₂₀)_(n)N(R_(10′))S(O)₂R₇, (CR₁₀R₂₀)_(n)NR_(e)R_(e′),        (CR₁₀R₂₀)_(n)NR_(e)R_(e′)C₁₋₄alkyl NR_(e)R_(e′),        (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR_(e)R_(e′),        (CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,        (CR₁₀R₂₀)_(n)C(Z)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆,        (CR₁₀R₂₀)_(n)N(R_(10′))C(═N(R_(10′)))NR_(e)R_(e′),        (CR₁₀R₂₀)_(n)C(═NOR₆)NR_(e)R_(e′),        (CR₁₀R₂₀)_(n)OC(Z)NR_(e)R_(e′),        (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR_(e)R_(e′), or        (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or heterocyclylC₁₋₁₀ alkyl moiety, and    -   wherein these moieties are all optionally substituted one or        more times, independently at each occurrence from hydrogen,        halogen, nitro, C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀        alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀        alkyl, C₅₋₇cycloalkenyl, C₅₋₇cycloalkenylC₁₋₁₀ alkyl,        (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇,        (CR₁₀R₂₀)_(n)N(R_(10′))S(O)₂R₇, (CR₁₀R₂₀)_(n)NR₁₆R₂₆,        (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR₁₆R₂₆, (CR₁₀R₂₀)_(n)C(Z)R₆,        (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,        (CR₁₀R₂₀)_(n)C(Z)NR₁₆R₂₆, (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆,        (CR₁₀R₂₀)_(n)N(R_(10′))C(═N(R_(10′)))NR₁₆R₂₆,        (CR₁₀R₂₀)_(n)OC(Z)NR₁₆R₂₆, (CR₁₀R₂₀)_(n)N(R_(10′)′)C(Z)NR₁₆R₂₆,        or (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or heteroaryl C₁₋₄ alkyl; or the R₄ and R₁₄ together with    the nitrogen which they are attached form an unsubstituted or    substituted heterocyclic ring of 4 to 7 members, which ring    optionally contains an additional heteroatom selected from oxygen,    sulfur or nitrogen; and    -   wherein the C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄        alkyl, aryl, aryl-C₁₋₄ alkyl, heteroaryl and heteroaryl C₁₋₄        alkyl moieties, and the R₄ and R₁₄ cyclized ring are optionally        substituted, 1 to 4 times, independently at each occurrence, by        halogen; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy;        halosubstituted C₁₋₁₀ alkoxy; C₁₋₁₀ alkyl; halosubstituted C₁₋₁₀        alkyl; SR₅; S(O)R₅; S(O)₂R₅; C(O)Rj; C(O)ORj;        C(O)NR_(4′)R_(14′); (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇;        (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR_(d)R_(d′); NR_(4′)C(O)C₁₋₁₀alkyl;        NR_(4′)C(O)aryl; NR_(4′)R_(14′); cyano; nitro; C₃₋₇cycloalkyl;        C₃₋₇cycloalkyl C₁₋₁₀ alkyl; an unsubstituted or substituted        aryl, or arylC₁₋₄ alkyl; an unsubstituted or substituted        heteroaryl, or heteroaryl C₁₋₄ alkyl; an unsubstituted or        substituted heterocyclic, or heterocyclic C₁₋₄ alkyl, and        wherein these aryl, heterocyclic and heteroaryl containing        moieties are substituted one to two times independently at each        occurrence by halogen; C₁₋₄ alkyl, hydroxy; hydroxy substituted        C₁₋₄ alkyl; C₁₋₄ alkoxy; S(O)_(m)alkyl; amino, mono &        di-substituted C₁₋₄ alkyl amino, or CF₃;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′) can    cyclize together with the nitrogen to which they are attached to    form a 5 to 7 membered ring which optionally contains an additional    heteroatom selected from oxygen, sulfur or NR_(9′);-   R_(4″) and R_(14″) are independently selected at each occurrence    from hydrogen or C₁₋₄ alkyl, or R_(4″) and R_(14″) together with the    nitrogen to which they are attached, cyclize to form a 5 to 7    membered ring which optionally contains an additional heteroatom    selected from oxygen, sulfur or NR_(9′);-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′,) S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R₆ is independently selected at each occurrence from hydrogen, C₁₋₁₀    alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀alkyl, aryl,    arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl, wherein each    of these moieties, excluding hydrogen are optionally substituted;-   R₇ is independently selected at each occurrence from C₁₋₆alkyl,    aryl, arylC₁₋₆alkyl, heterocyclic, heterocyclylC₁₋₆ alkyl,    heteroaryl, or heteroarylC₁₋₆alkyl moiety, and wherein each of these    moieties may be optionally substituted;-   R₈ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇ cycloalkyl C₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein these moieties, excluding hydrogen, may be    optionally substituted;-   R₉ is independently selected at each occurrence from hydrogen,    C(Z)R₆, optionally substituted C₁₋₁₀ alkyl, optionally substituted    aryl, optionally substituted aryl-C₁₋₄ alkyl;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R₁₀′ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇ cycloalkyl C₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or heterocyclylC₁₋₄ alkyl, and    wherein these moieties, excluding hydrogen, may be optionally    substituted;-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R₁₅ and R₂₅ are independently selected at each occurrence from    hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, or aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl    heteroaryl or heteroaryl C₁₋₄ alkyl moiety, and wherein these    moieties, excluding hydrogen may be optionally substituted; or R₁₅    and R₂₅ together with the nitrogen which they are attached form an    optionally substituted heterocyclic ring of 4 to 7 members, which    ring optionally contains an additional heteroatom selected from    oxygen, sulfur or NR₉; and    -   wherein these moieties, excluding hydrogen, are optionally        substituted 1 to 4 times, independently at each occurrence from        halogen; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy;        halosubstituted C₁₋₁₀ alkoxy; halosubstituted C₁₋₄ alkyl; SR₅,        S(O)R₅, S(O)₂R₅; C(O)R_(j); C(O)OR_(j); C(O)NR_(4′)R_(14′);        NR_(4′)C(O)C₁₋₁₀alkyl; NR_(4′)C(O)aryl; NR_(4′)R_(14′); cyano;        nitro; C₁₋₁₀ alkyl; C₃₋₇cycloalkyl; C₃₋₇cycloalkyl C₁₋₁₀ alkyl;        halosubstituted C₁₋₁₀ alkyl; aryl, aryl C₁₋₄ alkyl,        heterocyclic, heterocyclic C₁₋₄ alkyl, heteroaryl, or hetero        C₁₋₄ alkyl, and wherein these aryl, heterocyclic, and heteroaryl        containing moieties may also be substituted one to two times        independently at each occurrence by halogen, C₁₋₄ alkyl,        hydroxy, hydroxy substituted C₁₋₄ alkyl, C₁₋₁₀ alkoxy, S(O)_(m)        C₁₋₄ alkyl, amino, mono & di-substituted C₁₋₄ alkylamino, C₁₋₄        alkyl, or CF₃;-   R₁₆ and R₂₆ are each independently selected at each occurrence from    hydrogen, or C₁₋₄ alkyl; or the R₁₆ and R₂₆ together with the    nitrogen which they are attached form an unsubstituted or    substituted heterocyclic ring of 4 to 7 members, which ring    optionally contains an additional heteroatom selected from oxygen,    sulfur or NR_(9′);-   R_(21′) and R_(31′) are independently selected at each occurrence    from hydrogen or C₁₋₄ alkyl, or R_(21′) and R_(31′) together with    the nitrogen to which they are attached cyclize to form a 5 to 7    membered ring which optionally contains an additional heteroatom    selected from oxygen, sulfur or NR_(9′);-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl    moiety; and    -   which moieties may all be optionally substituted 1 to 4 times        independently at each occurrence from halogen; hydroxy; hydroxy        substituted C₁₋₁₀alkyl; C₁₋₁₀ alkyl; C₁₋₁₀ alkoxy;        halosubstituted C₁₋₁₀ alkoxy; OR₈, SR₅, S(O)R₅, S(O)₂R₅;        C(O)R_(j); C(O)OR_(j); C(O)NR₁₅R₂₅; cyano; nitro; NR₁₅R₂₅;        —Z′—(CR₁₀R₂₀)s-Z′—, C₃₋₇cycloalkyl; C₃₋₇cycloalkyl C₁₋₁₀ alkyl;        halosubstituted C₁₋₁₀ alkyl; an optionally substituted aryl or        arylalkyl, an optionally substituted heteroaryl and        heteroarylC₁₋₁₀ alkyl, and an optionally substituted        heterocyclic and heterocyclicC₁₋₁₀ alkyl, and wherein these        aryl, heteroaryl and heterocyclic containing moieties may also        be substituted one to two times independently at each occurrence        from halogen, hydroxy, hydroxy substituted alkyl, C₁₋₁₀ alkoxy,        S(O)_(m)C₁₋₄ alkyl, amino, mono & di-substituted C₁₋₄ alkyl        amino, C₁₋₄ alkyl, or CF₃;-   R_(d) and R_(d′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆    cycloalkylC₁₋₄alkyl, or the R_(d) and R_(d′) together with the    nitrogen which they are attached form an optionally substituted    heterocyclic ring of 5 to 6 members, which ring optionally contains    an additional heteroatom selected from oxygen, sulfur or NR_(9′);    and    -   wherein the R_(d) and R_(d′) moieties which are C₁₋₄ alkyl,        C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₄ alkyl, and the R_(d) and        R_(d′) cyclized ring are substituted, 1 to 4 times,        independently at each occurrence by halogen; halosubstituted        C₁₋₄ alkyl; hydroxy; hydroxy substituted C₁₋₄alkyl; C₁₋₄ alkoxy;        halosubstituted C₁₋₄ alkoxy; S(O)mRf; C(O)Rj; C(O)ORj;        C(O)NR_(4′)R_(14″); NR_(4′)C(O)C₁₋₄alkyl;        S(O)₂NR_(4′)R_(14′)C₁₋₄ alkyl; NR_(4′)R_(14′)S(O)₂C₁₋₄ alkyl; or        NR_(4′)R_(14′);-   R_(e) are R_(e′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₄alkyl, aryl, aryl-C₁₋₄ alkyl, heterocyclic,    heterocyclic C₁₋₄ alkyl, heteroaryl or a heteroaryl C₁₋₄ alkyl    moiety; or R_(e) and R_(e′) together with the nitrogen which they    are attached form an optionally substituted heterocyclic ring of 4    to 7 members, which ring optionally contains an additional    heteroatom selected from oxygen, sulfur or nitrogen; and    -   wherein each of these moieties, excluding hydrogen, may be        substituted 1 to 4 times, independently at each occurrence by        halogen; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy;        halosubstituted C₁₋₁₀ alkoxy; amino, mono & di-substituted C₁₋₄        alkyl amino; S(O)mR_(f); C(O)R_(j); C(O)ORj;        (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇;        (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR_(d)R_(d′); C(O)NR_(4′)R_(14′);        NR_(4′)C(O)C₁₋₁₀alkyl; NR_(4′)C(O)aryl; cyano; nitro; C₁₋₁₀        alkyl; C₃₋₇cycloalkyl; C₃₋₇cycloalkyl C₁₋₁₀ alkyl;        halosubstituted C₁₋₁₀ alkyl; aryl, aryl C₁₋₄ alkyl,        heterocyclic, heterocyclicC₁₋₄ alkyl, heteroaryl, or        heteroC₁₋₄alkyl, and wherein these aryl, heterocyclic, and        heteroaryl containing moieties may be optionally substituted one        to two times independently at each occurrence by halogen, C₁₋₄        alkyl, hydroxy, hydroxy substituted C₁₋₄ alkyl, C₁₋₁₀ alkoxy,        S(O)_(m)alkyl, amino, mono & di-substituted C₁₋₄ alkyl amino,        C₁₋₄ alkyl, or CF₃;-   R_(f) is independently selected at each occurrence from C₁₋₁₀alkyl,    aryl, aryl C₁₋₁₀alkyl, heteroaryl, heteroaryl C₁₋₁₀alkyl,    heterocyclic, or a heterocyclic C₁₋₁₀alkyl moiety, and wherein these    moieties may all be optionally substituted;-   R_(f′) is independently selected at each occurrence from hydrogen,    C₁₋₁₀alkyl, aryl, aryl C₁₋₁₀alkyl, heteroaryl, heteroaryl    C₁₋₁₀alkyl, heterocyclic, heterocyclic C₁₋₁₀alkyl or NR_(4′)R_(14′);    and wherein these moieties, excluding hydrogen, and NR_(4′)R_(14′),    may be optionally substituted;-   R_(j) is independently selected at each occurrence from hydrogen,    C₁₋₄alkyl, aryl, aryl C₁₋₄alkyl, heteroaryl, heteroaryl C₁₋₄alkyl,    heterocyclic, or a heterocyclic C₁₋₄alkyl moiety, and wherein these    moieties, excluding hydrogen, may be optionally substituted;-   g is 0, or integer having a value of 1, 2, 3, or 4;-   n is independently selected at each occurrence from 0 or an integer    having a value of 1 to 10;-   n′ is independently selected at each occurrence from 0 or an integer    having a value of 1 to 10;-   m is independently selected at each occurrence from 0 or an integer    having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6;-   v is 0 or an integer having a value of 1 or 2;-   v′ is independently selected at each occurrence from 0 or an integer    having a value of 1 or 2;-   s is independently selected at each occurrence from an integer    having a value of 1, 2, or 3;-   t is an integer having a value of 2 to 6;-   Z is independently selected at each occurrence from oxygen or    sulfur;-   Z′ is independently selected at each occurrence from oxygen, or    sulfur; and-   a pharmaceutically acceptable salt thereof, solvate or    physiologically functional derivative thereof.

Suitably, for compounds of Formula (I), and (Ia), and the remainingformulas described herein R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b),C(Z)O(CR₁₀R₂₀)_(v)R_(b), N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b),N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), orN(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b).

In one embodiment of the invention, R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), or N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b). In another embodiment of theinvention R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v) R_(b).

Suitably, R_(1′) is independently selected at each occurence fromhalogen, C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,(CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅, S(O)₂R₅,or (CR₁₀R₂₀)_(v′)OR₁₃.

In one embodiment, R_(1′) is independently selected at each occurrencefrom halogen, C₁₋₄ alkyl, or halo-substituted-C₁₋₄ alkyl. In anotherembodiment, R_(1′) is independently selected at each occurrence fromfluorine, chlorine, methyl, or CF₃.

Suitably, g is 0 or an integer having a value of 1, 2, 3, or 4. In oneembodiment of the invention, g is 0, 1 or 2.

For compounds of Formula (I) and (Ia), when R_(1′) is substituted on aphenyl ring in the ortho position, and a second R_(1′) moiety is alsosubstituted on the ring, then preferably the second substitution is notin the other ortho position. Suitably, the phenyl ring is substituted inthe 2-position and if a second substituent is present, in the 3-positionwith the R₁ moiety in the 5-position. Alternatively, the R_(1′) moietymay be in the other ortho 2-position and the R₁ moiety in the3-position, which will change the ring position numbering.

Suitably, R_(d) and R_(d′) are each independently selected at eachoccurrence from hydrogen, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₃₋₅cycloalkylC₁₋₄alkyl, or the R_(d) and R_(d′) together with the nitrogenwhich they are attached form an optionally substituted heterocyclic ringof 5 to 6 members, which ring optionally contains an additionalheteroatom selected from oxygen, sulfur or NR_(9′), and wherein theR_(d) and R_(d′) moieties which are C₁₋₄ alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylC₁₋₄ alkyl, and the R_(d) and R_(d′) cyclized ring areoptionally substituted, 1 to 4 times, independently at each occurrenceby halogen; halosubstituted C₁₋₄ alkyl; hydroxy; hydroxy substitutedC₁₋₄alkyl; C₁₋₄ alkoxy; halosubstituted C₁₋₄ alkoxy; S(O)mRf; C(O)Rj;C(O)ORj; C(O)NR_(4′)R_(14′), NR_(4′)C(O)C₁₋₄alkyl;S(O)₂NR_(4′)R_(14′)C₁₋₄ alkyl; NR_(4′)R_(14′)S(O)₂C₁₋₄ alkyl; orNR_(4′)R_(14′).

Suitably R_(9′) is independently selected at each occurrence fromhydrogen, or C₁₋₄ alkyl.

Suitably, Z is independently selected at each occurrence from oxygen orsulfur.

Suitably, v is 0 or an integer having a value of 1 to 2.

Suitably, v′ is 0 or an integer having a value of 1 or 2.

Suitably, R₁₀ and R₂₀ are independently selected at each occurrence fromhydrogen or C₁₋₄ alkyl.

Suitably, R_(10′) is independently selected at each occurrence fromhydrogen or C₁₋₄ alkyl.

Suitably, R₁₂ is independently selected at each occurrence fromhydrogen, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₄ alkyl, C₅₋₇ cycloalkenyl,C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,heteroarylC₁₋₄ alkyl, heterocyclyl, or heterocyclylC₁₋₄ alkyl, andwherein these moieties, excluding hydrogen, may be optionallysubstituted.

Suitably, R₁₃ is independently selected at each occurrence fromhydrogen, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl moiety,and wherein each of these moieties, excluding hydrogen, may beoptionally substituted and wherein these moieties, excluding hydrogen,may be optionally substituted 1 to 4 times by halogen; halosubstitutedC₁₋₄ alkyl; C₁₋₄ alkyl; hydroxy; hydroxy substituted C₁₋₄alkyl;C₁₋₄alkoxy; halosubstituted C₁₋₄ alkoxy; S(O)mC₁₋₄ alkyl; —C(O),C(O)C₁₋₄ alkyl; or NR_(21′)R_(31′).

Suitably, R_(21′) and R_(31′) are each independently selected at eachoccurrence from hydrogen or C₁₋₄ alkyl, or R_(21′) and R_(31′) togetherwith the nitrogen to which they are attached cyclize to form a 5 to 7membered ring which optionally contains an additional heteroatomselected from oxygen, nitrogen, or sulfur.

Suitably R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, whichmoieties, excluding hydrogen, are all optionally substituted.

The R_(b) moieties, excluding hydrogen, may be optionally substituted,one or more times, preferably 1 to 4 times independently at eachoccurrence by halogen, such as fluorine, chlorine, bromine or iodine;hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy, such as methoxyor ethoxy; halosubstituted C₁₋₁₀ alkoxy; OR₈, such as methoxy, ethoxy orphenoxy; SR₅, S(O)R₅, S(O)₂R_(5,) such as methyl thio, methylsulfinyl ormethyl sulfonyl; C(O)R_(j); C(O)OR_(j); C(O)NR_(4″)R_(14″); cyano;nitro; NR₁₅R₂₅; —Z′—(CR₁₀R₂₀)s-Z′; C₁₋₁₀alkyl; C₃₋₇cycloalkyl or aC₃₋₇cycloalkyl C₁₋₁₀ alkyl group, such as cyclopropyl, or cyclopropylmethyl, or cyclopropylethyl, etc.; halosubstituted C₁₋₁₀ alkyl, suchCF₂CF₂H, CH₂CF₃, or CF₃; an optionally substituted aryl, such as phenyl,or an optionally substituted arylC₁₋₁₀alkyl, such as benzyl orphenethyl; an optionally substituted heterocyclic or heterocyclicC₁₋₁₀alkyl, or an optionally substituted heteroaryl or heteroarylC₁₋₁₀alkyl, and wherein these aryl, heteroaryl, and heterocycliccontaining moieties may also be substituted one to two timesindependently at each occurrence by halogen, hydroxy, hydroxysubstituted C₁₋₄ alkyl, C₁₋₁₀ alkoxy, S(O)_(m)alkyl, amino, mono &di-substituted C₁₋₄ alkyl amino, C₁₋₄ alkyl, or CF₃.

The moiety —Z′—(CR₁₀R₂₀)s-Z′ forms a cyclic ring, such as a dioxalanering.

Suitably Z′ is independently selected at each occurrence from oxygen, orsulfur.

Suitably, s is independently selected at each occurrence from an integerhaving a value of 1, 2, or 3.

Suitably, R₅ is independently selected at each occurrence from hydrogen,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding themoieties SR₅ being SNR_(4′)R_(14′,) S(O)₂R₅ being SO₂H and S(O)R₅ beingSOH.

Suitably, R_(4′) and R_(14′) are each independently selected at eachoccurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′) cancyclize together with the nitrogen to which they are attached to form anoptionally substituted 5 to 7 membered ring which optionally contains anadditional heteroatom selected from oxygen, sulfur or NR_(9′). Suitably,when R_(4′) and R_(14′) cyclize to form an optionally substituted ring,such rings include, but are not limited to pyrrolidine, piperidine,piperazine, morpholine, and thiomorpholine (including oxidizing thesulfur).

Suitably, R_(4″) and R_(14″) are each independently selected at eachoccurrence from hydrogen or C₁₋₁₀ alkyl, or R_(4″) and R_(14″) cancyclize together with the nitrogen to which they are attached to form anoptionally substituted 5 to 7 membered ring which optionally contains anadditional heteroatom selected from oxygen, sulfur or NR_(9′). Suitably,when R_(4″) and R_(14″) cyclize to form an optionally substituted ring,such rings include, but are not limited to pyrrolidine, piperidine,piperazine, morpholine, and thiomorpholine (including oxidizing thesulfur).

Suitably, R_(f) is independently selected at each occurrence fromhydrogen, C₁₋₁₀alkyl, aryl, aryl C₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀alkyl, heterocyclic, or a heterocyclic C₁₋₁₀alkyl moiety, andwherein these moieties, excluding hydrogen, may be optionallysubstituted.

Suitably, R_(j) is independently selected at each occurrence fromC₁₋₁₀alkyl, aryl, aryl C₁₋₁₀alkyl, heteroaryl, heteroaryl C₁₋₁₀alkyl,heterocyclic, or a heterocyclic C₁₋₁₀alkyl moiety, which moieties mayall be optionally substituted.

Suitably, when R_(b) is an optionally substituted C₁₋₁₀alkyl, the moietyincludes but is not limited to a methyl, ethyl, n-propyl, isopropyl,t-butyl, n-butyl, isobutyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl,heptyl, 2-methylpropyl; a halosubstituted alkyl, such as2,2,2-trifluroethyl, trifluromethyl, 2-fluoroethyl; a cyano substitutedalkyl, such as cyanomethyl, cyanoethyl; an alkoxy, thio or hydroxysubstituted alkyl, such as 2-methoxy-ethyl, 2-hydroxy propyl or serinol,or an ethylthioethyl.

In an alternative embodiment, when R_(b) is an optionally substitutedC₁₋₁₀alkyl the moiety is a methyl, ethyl, n-propyl, isopropyl, t-butyl,n-butyl, or 2,2-dimethylpropyl or 2-hydroxy propyl group.

Suitably, when R_(b) is an optionally substituted heteroaryl, orheteroarylalkyl, the heteroaryl containing moiety includes but is notlimited to, furyl, pyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,oxathiadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and uracil, indolyl,isoindolyl, indazolyl, indolizinyl, azaindolyl, benzoxazolyl,benzimidazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl, quinolyl,isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl,purinyl, and phthalazinyl.

In one embodiment, when R_(b) is an optionally substituted heteroaryl itis a 1,3-thiazol-2-yl or 5-methyl-1,3-thiazol-2-yl, isoquinolinyl,thiophene, e.g. a 3-thiophene, indol-5-yl, pyridinyl, e.g. apyridin3-yl, or pyridine-4-yl, indazolyl, benzothiazolyl,2-methyl-1,3-benzothiazol-5-yl, 1H-imidazol-4-yl or1H-imidazol-4-ylethyl. Further to this, the heteroaryl ring is anoptionally substituted thiazolyl, pyridyl, or thiophene ring.Preferably, R_(b) is an optionally substituted 1,3-thiazol-2-yl.

Suitably, when R_(b) is an optionally substituted heterocyclic, orheterocyclicalkyl, the heterocyclic containing moiety includes but isnot limited to tetrahydropyrrole, tetrahydropyran, tetrahydrofuran,tetrahydrothiophene (including oxidized versions of the sulfur moiety),azepine, diazepine, aziridinyl, pyrrolinyl, pyrrolidinyl,2-oxo-1-pyrrolidinyl, 3-oxo-1-pyrrolidinyl, 1,3-benzdioxol-5-yl,imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl,piperidinyl, piperazinyl, morpholino and thiomorpholino (includingoxidized versions of the sulfur moiety). In one embodiment, theheterocyclic, or heterocyclic alkyl group is pyrazol-3-yl, 4-morpholino,unsubstituted and substituted 2-furanyl, or 2-furanylmethyl, 2-thienylor 2-thienylmethyl, tetrahydro-2H-pyran-4yl, or tetrahydro-2H-pyran-4ylmethyl, tetrahydro-2-furanyl, or tetrahydro-2-furanylmethyl.

Suitably, when R_(b) is an optionally substituted aryl or arylalkylmoiety, the aryl containing moiety is unsubstituted or substitutedindependently at each occurrence one or more times by halogen, alkyl,cyano, OR₈, SR₅, S(O)₂R₅, C(O)R_(j), C(O)OR_(j), —Z′—(CR₁₀R₂₀)s-Z′,halosubstituted C₁₋₁₀ alkyl, or an optionally substituted aryl.

In one embodiment, R_(b) is a phenyl, or napthylene, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,3-difluorphenyl, 2,4-diflurophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-chloro-4-fluorophenyl, 2-methyl phenyl, 3-methylphenyl,4-methylphenyl, 6-methyl phenyl, 2-methyl phenyl, 3-amino phenyl,3,4-dimethyl phenyl, 4-methyl-3-fluorophenyl, 4-trifluorophenyl,4-ethoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl,4-thiomethylphenyl, 4-acetylphenyl, 4-dimethylaminophenyl, benzyl,phenethyl, phenylpropyl, 2,3-difluoro-benzyl, 3,5-difluoro-benzyl,biphenyl, 4′-fluorobiphenyl, 4-sulfonamindo-2-methylphenyl, or3-phenyloxyphenyl, 4-phenyloxyphenyl, 4-(1-piperidinylsulfonyl)-phenyl,or 3-(aminocarbonyl)phenyl.

In another embodiment, R_(b) is a phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,4-diflurophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-chloro-4-fluorophenyl, 4-methyl-3-fluorophenyl, 4-trifluorophenyl,2-methylphenyl, 3-methylphenyl, 4-ethoxyphenyl, 4-methoxyphenyl,3-cyanophenyl, 4-cyanophenyl, 4-thiomethylphenyl, 4-acetylphenyl,4-dimethylaminophenyl, biphenyl, 4′-fluorobiphenyl,4-sulfonamindo-2-methylphenyl, 3-phenyloxyphenyl, benzyl, or phenethyl.Further to this R_(b) is a 4-fluorophenyl.

Suitably, when R_(b) is an optionally substituted cycloalkyl orcycloalkyl alkyl moiety, the moiety is a cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropylmethyl, or a cyclopentylmethyl. Inanother embodiment, R_(b) is a cyclopropyl or cyclopropylmethyl group.

In another embodiment, R_(b) is C₁₋₁₀ alkyl, heteroaryl, or aryl, alloptionally substituted.

In another embodiment, R_(b) is hydrogen, or an optionally substitutedalkyl.

In one embodiment of the invention R_(b) is an alkyl, such as propyl orisopropyl; heteroaryl, such as a thiazolyl; an aryl, such phenyl, or 4-Fphenyl; an arylalkyl, or a cycloalkylalkyl moiety, all optionallysubstituted. In another embodiment, R_(b) is alkyl, heteroaryl, or aryl,all optionally substituted.

Suitably, m is independently selected at each occurrence from 0 or aninteger having a value of 1 or 2.

For each of the integer variables where appropriate, e.g. n, n′, m, q′,s, t, or v′, etc. they are independently chosen at each occurrence.

Suitably, R₈ is independently selected at each occurrence from hydrogen,C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₄ alkyl, C₅₋₇ cycloalkenyl,C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl moiety,and wherein these moieties, excluding hydrogen, may be optionallysubstituted independently at each occurrence, 1 to 4 times, by halogen;halosubstituted C₁₋₄ alkyl; C₁₋₄ alkyl; C₃₋₅cyclo alkyl; C₃₋₅cyclo alkylC₁₋₄alkyl; halo substituted C₁₋₄ alkyl; hydroxy; hydroxy substitutedC₁₋₄alkyl; C₁₋₄alkoxy; halosubstituted C₁₋₄ alkoxy; S(O)mC₁₋₄ alkyl;—C(O), C(O)C₁₋₄ alkyl; NR_(21′)R_(31′); or an aryl or aryl C₁₋₄ alkyl,and wherein these aryl containing moieties may also be substituted oneto two times independently at each occurrence, by halogen, hydroxy,hydroxy substituted alkyl, C₁₋₄ alkoxy, S(O)_(m)C₁₋₄alkyl, amino, mono &di-substituted C₁₋₄ alkylamino, C₁₋₄ alkyl, or CF₃.

Suitably, R₁₅ and R₂₅ are each independently selected at each occurrencefrom hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,aryl, or aryl-C₁₋₄ alkyl, heteroaryl or heteroaryl C₁₋₄ alkyl moiety,and wherein these moieties, excluding hydrogen may be optionallysubstituted; or R₁₅ and R₂₅ together with the nitrogen which they areattached form an optionally substituted heterocyclic ring of 4 to 7members, which ring optionally contains an additional heteroatomselected from oxygen, sulfur or NR₉; and wherein these moieties areoptionally substituted 1 to 4 times, independently at each occurrence byhalogen; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy;halosubstituted C₁₋₁₀ alkoxy; SR₅, S(O)R₅, S(O)₂R₅; C(O)R_(j);C(O)OR_(j); C(O)NR_(4′)R_(14′); NR_(4′)C(O)C₁₋₁₀alkyl; NR_(4′)C(O)aryl;NR_(4′)R_(14′); cyano; nitro; C₁₋₁₀ alkyl; C₃₋₇cycloalkyl;C₃₋₇cycloalkyl C₁₋₁₀ alkyl; halosubstituted C₁₋₁₀ alkyl; aryl, arylC₁₋₄alkyl, heteroaryl, or heteroC₁₋₄ alkyl, heterocyclic andheterocyclicC₁₋₄ alkyl and wherein these aryl, heterocyclic andheteroaryl containing moieties may also be substituted one to two timesindependently at each occurrence by halogen, C₁₋₄ alkyl, hydroxy,hydroxy substituted C₁₋₄ alkyl, C₁₋₁₀ alkoxy, S(O)_(m)alkyl, amino, mono& di-substituted C₁₋₄ alkyl amino, C₁₋₄ alkyl, or CF₃.

Suitably, R₄ and R₁₄ are each independently selected at each occurrencefrom hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl, heteroarylor heteroaryl C₁₋₄ alkyl; or the R₄ and R₁₄ together with the nitrogenwhich they are attached form an unsubstituted or substitutedheterocyclic ring of 4 to 7 members, which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or nitrogen.

The R₄ and R₁₄ moieties, excluding hydrogen, of C₁₋₁₀ alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, aryl, aryl-C₁₋₄ alkyl,heteroaryl and heteroaryl C₁₋₄ alkyl moieties, heterocyclic, orheterocyclic C₁₋₄ alkyl moieties, and the R₄ and R₁₄ cyclized ring areoptionally substituted, one or more times, preferably 1 to 4 times,independently at each occurrence, by halogen; hydroxy; hydroxysubstituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy; halosubstituted C₁₋₁₀ alkoxy;C₁₋₁₀ alkyl; halosubstituted C₁₋₁₀ alkyl; SR₅; S(O)R₅; S(O)₂R₅; C(O)Rj;C(O)ORj; C(O)NR_(4′)R_(14′); (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇;(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR_(d)R_(d′); NR_(4′)C(O)C₁₋₁₀alkyl;NR_(4′)C(O)aryl; NR_(4′)R_(14′); cyano; nitro; C₃₋₇cycloalkyl;C₃₋₇cycloalkyl C₁₋₁₀ alkyl; C₁₋₁₀ alkyl substituted one or more times byan optionally substituted aryl; an unsubstituted or substituted aryl, orarylC₁₋₄ alkyl; an unsubstituted or substituted heteroaryl, orheteroaryl C₁₋₄ alkyl; an unsubstituted or substituted heterocyclic, orheterocyclic C₁₋₄ alkyl, and wherein these aryl, heterocyclic andheteroaryl containing moieties are substituted one to two timesindependently at each occurrence by halogen; C₁₋₄ alkyl, hydroxy;hydroxy substituted C₁₋₄ alkyl; C₁₋₄ alkoxy; S(O)_(m)alkyl; amino, mono& di-substituted C₁₋₄ alkyl amino, or CF₃.

Suitably, when R₄ and R₁₄ together with the nitrogen cyclize to form anoptionally substituted ring, such as described above, such ringsinclude, but are not limited to pyrrolidine, piperidine, piperazine,diazepine, morpholine, and thiomorpholine (including oxidizing thesulfur).

Suitably, R₆ is independently selected at each occurrence from hydrogen,C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀alkyl,aryl, arylC₁₋₁₀ alkyl, heteroaryl or a heteroarylC₁₋₁₀ alkyl moiety, andwherein these moieties, excluding hydrogen may be optionally substitutedindependently at each occurrence, one or more times, suitably 1 to 2times, by halogen; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀alkoxy; halosubstituted C₁₋₁₀ alkoxy; S(O)m alkyl; C(O); NR_(4′)R_(14′);C₁₋₁₀ alkyl; C₃₋₇cycloalkyl; C₃₋₇cycloalkyl C₁₋₁₀ alkyl; halosubstitutedC₁₋₁₀ alkyl; an unsubstituted or substituted aryl or aryl C₁₋₄ alkyl, anunsubstituted or substituted heteroaryl or heteroaryl C₁₋₄ alkyl, or aunsubstituted or substituted heterocyclic or heterocyclic C₁₋₄ alkyl,and wherein these aryl, heterocyclic, or heteroaryl containing moietiesmay be substituted independently at each occurrence, one or two times byhalogen, hydroxy, hydroxy substituted alkyl, C₁₋₁₀ alkoxy,S(O)_(m)alkyl, amino, mono & di-substituted C₁₋₄ alkyl amino, C₁₋₄alkyl, or CF₃.

Suitably, R₉ is independently selected at each occurrence from hydrogen,C(Z)R₆, optionally substituted C₁₋₁₀ alkyl, optionally substituted arylor optionally substituted aryl-C₁₋₄ alkyl. These alkyl, aryl andarylalkyl moieties may be optionally substituted 1 or 2 times,independently at each occurrence by halogen; hydroxy; hydroxysubstituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy; halosubstituted C₁₋₁₀ alkoxy;S(O)m alkyl; —C(O); NR_(4′)R_(14′); C₁₋₁₀ alkyl, C₃₋₇cycloalkyl;C₃₋₇cycloalkyl C₁₋₁₀ alkyl; halosubstituted C₁₋₁₀ alkyl; an aryl or arylC₁₋₄ alkyl, and wherein these aryl containing moieties may also besubstituted one or two times independently by halogen, hydroxy, hydroxysubstituted alkyl, C₁₋₁₀ alkoxy, S(O)_(m)C₁₋₄ alkyl, amino, mono &di-substituted C₁₋₄ alkyl amino, C₁₋₄ alkyl, or CF₃.

Suitably, R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,heterocyclic, or heterocyclylC₁₋₁₀ alkyl moiety, which moieties may beoptionally substituted one ore more times, suitably 1 to 4 times,independently at each occurrence by hydrogen, halogen, nitro, C₁₋₁₀alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇cycloalkenyl,C₅₋₇cycloalkenylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH,(CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)N(R_(10′))S(O)₂R₇,(CR₁₀R₂₀)_(n)NR₁₆R₂₆, (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR₁₆R₂₆,(CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z)NR₁₆R₂₆, (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆,(CR₁₀R₂₀)_(n)N(R_(10′))C(═N(R_(10′)))NR₁₆R₂₆, (CR₁₀R₂₀)_(n)OC(Z)NR₁₆R₂₆,(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR₁₆R₂₆, or (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇.

In one embodiment, the R₃ moieties are optionally substituted 1 to 4times, independently at each occurrence by halogen, nitro, C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylC₁₋₄ alkyl, C₅₋₆cycloalkenyl, C₅₋₆cycloalkenylC₁₋₄ alkyl,(CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇,(CR₁₀R₂₀)_(n)NHS(O)₂R₇, (CR₁₀R₂₀)_(n)S(O)₂NR₁₆R₂₆, (CR₁₀R₂₀)_(n)NR₁₆R₂₆,(CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆,(CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆, or(CR₁₀R₂₀)_(n)C(Z)NR₁₆R₂₆.

In one embodiment the R₃ moieties are optionally substitutedindependently, one or more times, suitably 1 to 4 times, independentlyat each occurrence by the R₃ optional substitutent is independentlyselected from halogen, C₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₆,(CR₁₀R₂₀)_(n)NR₁₆R₂₆, or halo-substituted C₁₋₁₀ alkyl.

In another embodiment the optional substitutents are independentlyselected at each occurrence from halogen, C₁₋₁₀ alkyl, hydroxy, C₁₋₁₀alkoxy, cyano, nitro, amino, or halosubstituted C₁₋₁₀ alkyl. In anotherembodiment, the R₃ substituents are selected independently from halogen,such as fluorine, chlorine, bromine or iodine, or C₁₋₁₀ alkyl, such asmethyl.

In one embodiment the R₃ moieties are an optionally substituted C₁₋₁₀alkyl, optionally substituted C₃₋₇cycloalkyl, optionally substitutedC₃₋₇cycloalkylalkyl, or optionally substituted aryl. In anotherembodiment, the R₃ moiety is an optionally substituted C₁₋₁₀ alkyl, oran optionally substituted aryl. In another embodiment, R₃ is anoptionally substituted phenyl. Further to this embodiment, R₃ is aphenyl ring substituted one or more times by independently at eachoccurrence by fluorine, chlorine, hydroxy, methoxy, amino, methyl, ortrifluoromethyl. Preferably, R₃ is a 2,6-difluorophenyl.

Suitably, in one embodiment when R₃ is an aryl moiety, it is anoptionally substituted phenyl ring. The phenyl is optionally substitutedone or more times, independently at each occurrence, suitably 1 to 4times by halogen, C₁₋₄ alkyl, or halo-substituted-C₁₋₄ alkyl. The phenylring may be substituted in the 2, 4, or 6-position, or di-substituted inthe 2,4-position or 2,6-position, such as 2-fluoro, 4-fluoro,2,4-difluoro, 2,6-difluoro, or 2-methyl-4-fluoro; or tri-substituted inthe 2,4,6-position, such as 2,4,6-trifluoro.

Suitably, R₇ is independently selected at each occurrence fromC₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic, heterocyclylC₁₋₆ alkyl,heteroaryl, or heteroarylC₁₋₆alkyl; and wherein each of these moietiesmay be optionally substituted one or two times independently at eachoccurrence, by halogen; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀alkoxy; halosubstituted C₁₋₁₀ alkoxy; S(O)m alkyl; C(O); NR_(4′)R_(14′);C₁₋₁₀ alkyl; C₃₋₇cycloalkyl; C₃₋₇cycloalkylC₁₋₁₀ alkyl; halosubstitutedC₁₋₁₀ alkyl; an aryl or aryl C₁₋₄ alkyl moiety, and wherein these arylcontaining moieties may also be substituted independently at eachoccurrence, one to two times by halogen, hydroxy, hydroxy substitutedalkyl, C₁₋₁₀ alkoxy, S(O)_(m)alkyl, amino, mono & di-substituted C₁₋₄alkyl amino, C₁₋₄ alkyl, or CF₃.

Suitably, R₁₆ and R₂₆ are each independently selected at each occurrencefrom hydrogen, or C₁₋₄ alkyl; or the R₁₆ and R₂₆ together with thenitrogen which they are attached form an unsubstituted or substitutedheterocyclic ring of 4 to 7 members, which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR_(9′).

Suitably, n is 0, or an integer having a value of 1 to 10.

Suitably, X is R₂, OR_(2′), S(O)_(m)R_(2′), (CH₂)_(n)N(R₁₁)S(O)mR_(2′),(CH₂)_(n)N(R₁₁)C(O)R_(2′), (CH₂)_(n)NR₄R₁₄, (CH₂)_(n)N(R_(2′))(R_(2″)),or N(R_(10′))R_(h)NH—C(═N—CN)NRqRq′.

In one embodiment of the invention X isN(R_(10′))R_(h)NH—C(═N—CN)NRqRq′.

Suitably, X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀. In one embodiment ofthe invention, X₁ is N(R₁₁), or 0.

Suitably, R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,—CH₂—C(O)—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,—CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—, or—CH₂—CH₂—O—C(O)CH₂—.

Suitably, R_(q) and R_(q′) are independently selected at each occurrencefrom hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl,heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀alkyl moiety, and wherein all of the moieties, excluding hydrogen, areoptionally substituted, or R_(q) and R_(q′) together with the nitrogento which they are attached form an optionally substituted heterocyclicring of 5 to 7 members, which ring may contain an additional heteroatomselected from oxygen, nitrogen or sulphur.

Suitably, R₁₁ is independently selected at each occurrence fromhydrogen, or C₁₋₄ alkyl.

Suitably, R₂ is independently selected from hydrogen, optionallysubstituted C₁₋₁₀ alkyl, optionally substituted C₃₋₇ cycloalkyl,optionally substituted C₃₋₇cycloalkylalkyl, optionally substituted aryl,optionally substituted arylC₁₋₁₀alkyl, optionally substitutedheteroaryl, optionally substituted heteroarylC₁₋₁₀ alkyl, optionallysubstituted heterocyclic, optionally substituted heterocyclylC₁₋₁₀alkylmoiety; or R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃),or (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃).

Suitably q′ is 0, or an integer having a value of 1 to 6.

The R₂ moieties, excluding hydrogen, may be optionally substituted oneor more times, preferably 1 to 4 times, independently at each occurrenceby C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, C₅₋₇cycloalkenyl,C₅₋₇ cycloalkenyl C₁₋₁₀ alkyl, halogen, —C(O), cyano, nitro, aryl, arylC₁₋₁₀ alkyl, heterocyclic, heterocyclic C₁₋₁₀ alkyl, heteroaryl,heteroaryl C₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH,(CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)N(R_(10′))S(O)₂R₇,(CR₁₀R₂₀)_(n)NR_(e)R_(e′),(CR₁₀R₂₀)_(n)NR_(e)R_(e′)C₁₋₄alkylNR_(e)R_(e′), (CR₁₀R₂₀)_(n)CN,(CR₁₀R₂₀)_(n)S(O)₂NR_(e)R_(e′), (CR₁₀R₂₀)_(n)C(Z)R₆,(CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆,(CR₁₀R₂₀)_(n)N(R_(10′))C(═N(R_(10′)))NR_(e)R_(e′),(CR₁₀R₂₀)_(n)C(═NOR₆)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)OC(Z)NR_(e)R_(e′),(CR₁₀R₂₀)_(n)N(R_(10′))C(Z) NR_(e)R_(e′), or(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇.

Suitably, R_(e) and R_(e′) are each independently selected at eachoccurrence from hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclicC₁₋₄ alkyl, heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, which moietiesmay be optionally substituted; or R_(e) and R_(e′) together with thenitrogen which they are attached form an optionally substitutedheterocyclic ring of 4 to 7 members, which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or nitrogen; andwherein each of these moieties, including the cyclized ring andexcluding hydrogen, may be substituted 1 to 4 times, independently ateach occurrence by halogen; hydroxy; hydroxy substituted C₁₋₁₀alkyl;C₁₋₁₀ alkoxy; halosubstituted C₁₋₁₀ alkoxy; C₁₋₁₀ alkyl; halosubstitutedC₁₋₄ alkyl; S(O)mR_(f); C(O)R_(j); C(O)ORj; (CR₁₀R₂₀)_(n)N(R10′)C(Z)OR₇;(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR_(d)R_(d′); C(O)NR_(4′)R_(14′);NR_(4′)C(O)C₁₋₁₀alkyl; NR_(4′)C(O)aryl; cyano; nitro; NR_(4′)R_(14′);C₁₋₁₀ alkyl; C₃₋₇cycloalkyl; C₃₋₇cycloalkyl C₁₋₁₀ alkyl; halosubstitutedC₁₋₁₀ alkyl; aryl, arylC₁₋₄alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,heteroaryl, or hetero C₁₋₄ alkyl, and wherein these aryl, heterocyclicor heteroaryl containing moieties may be optionally substituted one totwo times independently at each occurrence by halogen, C₁₋₄ alkyl,hydroxy, hydroxy substituted C₁₋₄ alkyl, C₁₋₁₀ alkoxy, S(O)_(m)alkyl,amino, mono & di-substituted C₁₋₄ alkyl amino, C₁₋₄ alkyl, or CF₃.

Suitably, R_(f′) is independently selected at each occurrence fromhydrogen, C₁₋₁₀alkyl, aryl, aryl C₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀alkyl, heterocyclic, heterocyclic C₁₋₁₀alkyl or NR_(4′)R_(14′); andwherein these moieties, excluding hydrogen, and NR_(4′)R_(14′), may beoptionally substituted.

When X is R₂ and R₂ is an optionally substituted heterocyclic orheterocyclic alkyl, the heterocyclic containing moiety is suitablyselected from tetrahydropyrrole, tetrahydropyran, tetrahydrofuran,tetrahydrothiophene (including oxidized versions of the sulfur moiety),aziridinyl, pyrrolinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl,3-oxo-1-pyrrolidinyl, 1,3-benzdioxol-5-yl, imidazolinyl, imidazolidinyl,indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl,morpholino and thiomorpholino (including oxidized versions of the sulfurmoiety).

In one embodiment, R₂ is an optionally substituted piperidinyl orpiperazinyl ring.

In another embodiment, when R₂ is an optionally substituted heterocyclicor heterocyclic alkyl ring the ring is substituted one or mores timesindependently by an optionally substituted heterocyclic, heterocyclicalkyl, aryl, arylalkyl, alkyl, (CR₁₀R₂₀)_(n)NR_(e)R_(e′), or(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇. The second heterocyclic ring is suitablyselected from an optionally substituted tetrahydropyrrole,tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (includingoxidized versions of the sulfur moiety), aziridinyl, pyrrolinyl,pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 3-oxo-1-pyrrolidinyl,1,3-benzdioxol-5-yl, imidazolinyl, imidazolidinyl, indolinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, diazepine,morpholino or thiomorpholino (including oxidized versions of the sulfurmoiety). Suitably, the second heterocyclic ring is selected frommorpholino, piperidine, or pyrrolidinyl.

In one embodiment, R₂ is a 4-amino-1-piperidinyl,1,1-dimethylethyl)oxy]-carbonyl}amino)-1-piperidinyl,4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-propyl-1-piperazinyl,4-butyl-1-piperazinyl, 4-(methylamino)-1-piperidinyl,1,1-dimethylethyl-4-piperidinyl}methylcarbamate, 4-phenyl-1-piperazinyl,1,4′-bipiperidin-1′-yl, 4-(1-pyrrolidinyl)-1-piperidinyl,4-methyl-1,4′-bipiperidin-1′-yl, 4-(4-morpholinyl)-1-piperidinyl,4-(diphenylmethyl)-1-piperazinyl, or4-methylhexahydro-1H-1,4-diazepin-1-yl.

Suitably, R_(2′) is independently selected at each occurrence fromhydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl, aryl,arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or aheterocyclylC₁₋₁₀ alkyl moiety, and wherein each of these moieties,excluding hydrogen, may be optionally substituted 1 to 4 times,independently, at each occurrence, by C₁₋₁₀ alkyl, halo-substitutedC₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl,C₃₋₇cycloalkylC₁₋₁₀alkyl, C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenylC₁₋₁₀alkyl, halogen, —C(O), cyano, nitro, aryl, aryl C₁₋₁₀ alkyl, heteroaryl,heteroarylC₁₋₁₀ alkyl, heterocyclic, heterocyclylC₁₋₁₀ alkyl,(CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇,(CR₁₀R₂₀)_(n)N(R_(10′))S(O)₂R₇, (CR₁₀R₂₀)_(n)NR_(e)R_(e′),(CR₁₀R₂₀)_(n)NR_(e)R_(e′)C₁₋₄alkylNR_(e)R_(e′), (CR₁₀R₂₀)_(n)CN,(CR₁₀R₂₀)_(n)S(O)₂NR_(e)R_(e′), (CR₁₀R₂₀)_(n)C(Z)R₆,(CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆,(CR₁₀R₂₀)_(n)N(R_(10′))C(═N(R10′))NR_(e)R_(e′),(CR₁₀R₂₀)_(n)C(═NOR₆)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)OC(Z)NR_(e)R_(e′),(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR_(e)R_(e′), or(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇.

In one embodiment, when X is (CH₂)_(n)N(R_(2′))(R_(2″)), one of R_(2′),or R_(2″) is hydrogen, or methyl.

In one embodiment, when R_(2′) is an optionally substituted heterocyclicor heterocyclylC₁₋₁₀ alkyl the heterocyclic containing moiety issubstituted one or more time independently by C₁₋₁₀ alkyl, aryl,heteocyclic, (CR₁₀R₂₀)_(n)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇,or (CR₁₀R₂₀)_(n)C(Z)OR₆. More specifically, methyl, ethyl, NHC(O)O—CCH₃,N(CH₃)C(O)O—CCH₃, amino, methylamino, dimethylamino, phenyl, piperidine,pyrrolidine, 1-ethylpropyl, 4-methyl-1,4′-bipiperidin-1′-yl,1,4′-bipiperidin-1′-yl, morpholino,

In one embodiment, when X is (CH₂)_(n)N(R_(2′))(R_(2′)), R_(2′) is anoptionally substituted C₁₋₁₀ alkyl, cycloalkyl, heterocyclic,heterocyclyl C₁₋₁₀ alkyl, heteroarylalkyl. Suitably, when R_(2′) is anoptionally substituted cycloalkyl it is a cyclohexyl ring. In oneembodiment the cyclohexyl ring is optionally substituted one or moretimes by (CR₁₀R₂₀)_(n)NR_(e)R_(e′).

Suitably, when R_(2′) is an optionally substituted heterocyclic, or aheterocyclylC₁₋₁₀ alkyl, the ring is selected from tetrahydropyrrole,tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (includingoxidized versions of the sulfur moiety), aziridinyl, pyrrolinyl,pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 3-oxo-1-pyrrolidinyl,1,3-benzdioxol-5-yl, imidazolinyl, imidazolidinyl, indolinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, diazepine,hexahydro-1-H-azepine, morpholino or thiomorpholino (including oxidizedversions of the sulfur moiety). Preferably, the ring is a piperidine,piperazine, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, morpholino,hexahydro-1-H-azepine ring. In one embodiment, the rings are substitutedone or more times, suitably 1 to 4 times, independently by C₁₋₁₀ alkyl,aryl, arylalkyl, (CR₁₀R₂₀)_(n)NR_(e)R_(e′), or(CR₁₀R₂₀)_(n)N(R10′)C(Z)OR₇.

In one embodiment, (CH₂)_(n)N(R_(2′))(R_(2″)) is1-(phenylmethyl)-4-piperidinamine,2-[4-(phenylmethyl)-1-piperazinyl]ethylamine,2-(1-piperidinyl)ethylamine, 2-(1-methyl-2-pyrrolidinyl)ethylamine,1-[(phenylmethyl)-3-pyrrolidinyl]amine, 3-[(1-pyrrolidinyl)propyl]amine,3-[(hexahydro-1H-azepin-1-yl)propyl]amine,(1-methyl-4-piperidinyl)amine, 3-[(4-morpholinyl)propyl]amine,3-[(2-oxo-1-pyrrolidinyl)propyl]-amine, 2-[(4-morpholinyl)ethyl]amine,2-[(1-pyrrolidinyl)ethyl]-amine, or[(1-ethyl-2-pyrrolidinyl)methyl]amino.

In one embodiment when X is (CH₂)_(n)N(R_(2′))(R_(2″)), and R_(2′) is anoptionally substituted C₁₋₁₀ alkyl, the alkyl is substituted one or moretimes independently by (CR₁₀R₂₀)_(n)NR_(e)R_(e′) or(CR₁₀R₂₀)_(n)NR_(e)R_(e′)C₁₋₄alkylNR_(e)R_(e′). In one embodiment R_(e)and and R_(e′) are independently an optionally substituted C₁₋₄ alkyl,such as methyl, ethyl, isopropyl, n-butyl, or t-butyl. Preferably,(CH₂)_(n)N(R_(2′))(R_(2″)) is 3-(dimethylamino)propyl(methyl)amine,3-(diethylamino)propylamine, propylamine, (2,2-dimethylpropyl)amine,(2-hydroxypropyl)amino, 2-(dimethylamino)ethylamine,2-(dimethylamino)ethyl(methyl)amine, 3-(dimethylamino)propylamine,2-(dimethylamino)ethyl(methyl)amine, 3-(diethylamino)propylamine,2-(methylamino)ethylamine, [(1-methylethyl)amino]ethylamine,3-(diethylamino)propylamine, 3-(dibutylamino)propylamine,3-[(1-methylethyl)amino]propylamine,3-(1,1-dimethylethyl)aminopropylamine,3-(dimethylamino)-2,2-dimethylpropylamine,4-(diethylamino)-1-methylbutylamine, or3-[[3-(dimethylamino)propyl]-(methyl)amino]propyl(methyl)amine.

Suitably R_(2″) is selected from hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl,C₃₋₇cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and whereinthese moieties, excluding hydrogen, may be optionally substituted 1 to 4times, independently at each occurrence, by C₁₋₁₀ alkyl,halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₋₁₀alkyl, C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenylC₁₋₁₀ alkyl, halogen, —C(O), cyano, nitro, aryl, aryl C₁₋₁₀ alkyl,heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, heterocyclylC₁₋₁₀alkyl, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇,(CR₁₀R₂₀)_(n)N(R_(10′))S(O)₂R₇, (CR₁₀R₂₀)_(n)NR_(e)R_(e′),(CR₁₀R₂₀)_(n)NR_(e)R_(e′)C₁₋₄alkylNR_(e)R_(e′), (CR₁₀R₂₀)_(n)CN,(CR₁₀R₂₀)_(n)S(O)₂NR_(e)R_(e′), (CR₁₀R₂₀)_(n)C(Z)R₆,(CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆,(CR₁₀R₂₀)_(n)N(R_(10′))C(═N(R10′)) NR_(e)R_(e′),(CR₁₀R₂₀)_(n)C(═NOR₆)NR_(e)R_(e′), (CR₁₀R₂₀)_(n)OC(Z)NR_(e)R_(e′),(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR_(e)R_(e′), or(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇; or wherein R_(2″) is the moiety(CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);

Suitably, t is an integer having a value of 2 to 6.

Suitably, q is 0 or an integer having a value of 1 to 10.

Suitably, A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl, oraryl C₁₋₁₀ alkyl.

Suitably, A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl, oraryl C₁₋₁₀ alkyl.

Suitably, A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl.

The A₁, A₂, and A₃ C₁₋₁₀ alkyl moieties may optionally substituted oneor more times independently at each occurrence, preferably from 1 to 4times, with halogen, such as chlorine, fluorine, bromine, or iodine;halo-substituted C₁₋₁₀alkyl, such as CF₃, or CHF₂CF₃; C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenylC₁₋₁₀alkyl, (CR₁₀R₂₀)_(n)OR₆,(CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇,(CR₁₀R₂₀)_(n)N(R_(10′))S(O)₂R₇, (CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)CN,(CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆,(CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)R₆,(CR₁₀R₂₀)_(n)N(R_(10′))C(═N(R_(10′)))NR₄R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇.

In another embodiment of the present invention, X is R₂, and R₂ is(CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or(CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃). In a further embodiment, q′ is 0.

In another embodiment when R₂ is the moiety(CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), q′ is 0, X₁ is nitrogen, qis 0 or 1, A₁ is an optionally substituted heterocyclic or heterocyclicalkyl, and A₂ is an optionally substituted aryl. More specifically, R₂is 2-phenyl-2-(1-pyrrolidinyl)ethyl]amino, or1-phenyl-2-(1-pyrrolidinyl)ethyl]amino.

In one embodiment of the invention, one or more of the A₁, A₂ and A₃moieties are substituted with (CR₁₀R₂₀)_(n)OR₆. In another embodiment ofthe invention, the R₆ substituent in (CR₁₀R₂₀)_(n)OR₆ is hydrogen.

In yet another embodiment of the present invention, X is R₂ and R₂ is(CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃), such as CH(CH₂OH)₂, or C(CH₃)(CH₂OH)₂; orwherein R₂ is (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃) and q′ is 0,and the moiety is X₁(CR₁₀R₂₀)qCH(CH₂OH)₂, or X₁(CR₁₀R₂₀)qC(CH₃)(CH₂OH)₂;in another embodiment X₁ is oxygen or nitrogen.

In one embodiment of the present invention X is R₂, OR_(2′),(CH₂)_(n)NR₄R₁₄, or (CH₂)_(n)N(R_(2′))(R_(2″)).

In another embodiment X is S(O)_(m)R_(2′), (CH₂)_(n)NR₄R₁₄, or(CH₂)_(n)N(R_(2′))(R_(2″)).

In yet another embodiment, X is (CH₂)_(n)NR₄R₁₄, or(CH₂)_(n)N(R_(2′))(R_(2″)).

In yet another embodiment, X is (CH₂)_(n)NR₄R₁₄.

In yet another embodiment, X is (CH₂)_(n)N(R_(2′))(R_(2″)).

In one embodiment of the present invention X is R₂, OR_(2′),(CH₂)_(n)NR₄R₁₄, or (CH₂)_(n)N(R_(2′))(R_(2″)).

Suitably, when X is (CH₂)_(n)NR₄R₁₄, and R₄ and R₁₄ are C₁₋₁₀ alkyl,aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl, heteroarylor heteroaryl C₁₋₄ alkyl, the C₁₋₄ alkyl is suitably substituted one ormore times, independently at each occurrence with NR_(4′)R_(14′);halogen, hydroxy, alkoxy, C(O)NR_(4′)R_(14′); or NR_(4′)C(O)C₁₋₁₀alkyl.Preferably, the C₁₋₄ alkyl is substituted with NR_(4′)R_(14′).

In one embodiment at least one of R₄ and R₁₄ may be hydrogen when R₄ andR₁₄ are not cyclized. In another embodiment neither R₄ nor R₁₄ ishydrogen.

In one embodiment when X is (CH₂)_(n)NR₄R₁₄, one of R₄ and R₁₄ arehydrogen, and the other is an optionally substituted heteroaryl C₁₋₄alkyl. Suitably, the optionally substituted heteroaryl alkyl is animidazolyl alkyl, such as a 1H-imidazol-2-yl-methyl group.

In another embodiment when X is (CH₂)_(n)NR₄R₁₄ and one of R₄ and R₁₄ isa heteroaryl C₁₋₄ alkyl moiety, the heteroaryl ring is selected from anoptionally substituted thienyl, pyrrolyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, andbenzothiazolyl. Suitably, the heteroaryl C₁₋₄ alkyl is selected from anoptionally substituted pyrrolyl, oxazolyl, thiazolyl, isoxazolyl,imidazolyl, benzoxazolyl, benzimidazolyl, and benzothiazolyl.

In another embodiment when X is (CH₂)_(n)NR₄R₁₄ and one of R₄ and R₁₄ isa heterocyclic C₁₋₄ alkyl moiety, then the heterocyclic ring is selectedfrom an optionally substituted tetrahydropyrrole, tetrahydropyran,tetrahydrofuran, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl,indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, andmorpholino. Suitably, the heterocyclic C₁₋₄ alkyl moiety is selected anoptionally substituted from pyrrolinyl, pyrrolidinyl, piperidinyl,piperazinyl, and morpholino.

In another embodiment when X is (CH₂)_(n)NR₄R₁₄ and R₄ and R₁₄ togetherwith the nitrogen cyclize to form an optionally substituted ring, suchas described above, such rings include, but are not limited topyrrolidine, piperidine, piperazine, diazepine, and morpholine.

In one embodiment when X is (CH₂)_(n)NR₄R₁₄, the R₄ and R₁₄ substituentscyclize to form a heterocyclic 5 or 6 membered ring, which ring isoptionally substituted as defined herein. When the R₄ and R₁₄substituents cyclize to form a 4 to 7 membered ring, the optionalsubstitutents are suitably selected from an optionally substitutedalkyl, an optionally substituted aryl, an optionally substitutedheteroaryl, optionally substituted heterocyclic,(CR₁₀R₂₀)_(n)N(R_(10′))C(Z)OR₇, NR_(4′)R_(14′), or a C₁₋₁₀ alkylsubstituted one or more times by an optionally substituted aryl. Suchsubstitutents more specifically include phenyl, pyrrolidinyl,morpholino, piperazinyl, 4-methyl-1-piperazinyl, piperidinyl,2-oxo-2,3-dihydro-1H-benzimidazol-1-yl,5-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl, diphenylmethyl, methyl,ethyl, propyl, butyl, amino, methylamino, and dimethylamino.

In one embodiment the X substituent is a 1,4′-bipiperin-1-yl ring whichmay be optionally substituted such as in 4-methyl-1,4′-bipiperin-1-yl;4-piperidinylamino, 4-amino-1-piperidinyl,2,2,6,6-tetramethyl-4-piperidinyl)amino, 4-methyl-1-piperazinyl,(4-morpholinyl)-1-piperidinyl, (4-methyl-1-piperazinyl)-1-piperidinyl,4-ethyl-1-piperazinyl,(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl,5-chloro-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl,4-(1-pyrrolidinyl)-1-piperidinyl, 4-(diphenylmethyl)-1-piperazinyl,4-methylhexahydro-1H-1,4-diazepin-1-yl, 4-propyl-1-piperazinyl, or4-butyl-1-piperazinyl. In a further embodiment, the X substituent is anoptionally substituted 1,4′-bipiperin-1′yl ring, a4-amino-1-piperidinyl, or a 2,2,6,6-tetramethyl-4-piperidinyl)amino.

In another embodiment, when X is (CH₂)_(n)N(R_(2′))(R_(2″)), and R_(2′)is an optionally substituted C₁₋₁₀ alkyl moiety, and the alkyl issubstituted by (CR₁₀R₂₀)_(n)NR_(e)R_(e′), and R_(e) and R_(e′) arehydrogen, or an optionally substituted C₁₋₁₀ alkyl. Suitably, the Xmoiety is 3-(diethylamino)propylamino,3-(dimethylamino)propyl(methyl)amino,3-(dimethylamino)propyl(methyl)amino, 2-(dimethylamino)ethylamino,1-(methylethyl)amino-propylamino, (1,1-dimethylethyl)aminopropylamino,(1-methylethyl)aminoethylamino, 2-(methylamino)ethylamino,2-aminoethyl(methyl)amino, or a 2-(dimethylamino)ethyl(methyl)amino.

In another embodiment when X is (CH₂)_(n)N(R_(2′))(R_(2″)), and R_(2′)moiety is an optionally substituted heteroarylC₁₋₁₀ alkyl, theheteroaryl moiety is suitably an optionally substituted imidazole.

In one embodiment of the invention at least one of R₄ and R₁₄ may behydrogen when R₄ and R₁₄ are not cyclized.

In one embodiment R₃ is a 2,6-difluoro phenyl, R_(1′) is independentlyselected at each occurrence from hydrogen, fluorine, or methyl; g is 1or 2; and R₁ is selected from C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), orC(Z)O(CR₁₀R₂₀)_(v)R_(b), or N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b). Further tothis embodiment, R₁ is selected from C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b).In another embodiment, the R_(b) moiety is selected from thiazolyl,C₁₋₁₀ alkyl or an optionally substituted aryl. In another embodiment theR_(b) moiety is propyl or 4-fluorophenyl.

In another embodiment, X is suitably selected from(1H-imidazol-2-ylmethyl)amino or 4-methyl-1,4′-bipiperidin-1′-yl,2,2,6,6-tetramethyl-4-piperidinyl)amino, 4-amino-1-piperidinyl,3-(diethylamino)propylamino, 3-(dimethylamino)propyl(methyl)amino,3-(dimethylamino)propyl(methyl)amino, 2-(dimethylamino)ethylamino,1-methylethyl)amino-propylamino, (1,1-dimethylethyl)aminopropylamino,(1-methylethyl)aminoethylamino, 2-(methylamino)ethylamino,2-aminoethyl(methyl)amino, or 2-(dimethylamino)ethyl(methyl)amino.

In one embodiment, R₃ is a 2,6-difluoro phenyl, R_(1′) is independentlyselected at each occurrence from hydrogen, fluorine, or methyl; g is 1or 2; and R₁ is selected from C(Z)N(R10′)(CR₁₀R₂₀)_(v)R_(b), R_(b)moiety is C₁₋₁₀ alkyl or an optionally substituted aryl, preferablypropyl or 4-fluorophenyl, X is (CH₂)_(n)N(R_(2′))(R_(2″)), and n is 0.In another embodiment, X is (CH₂)_(n)N(R_(2′))(R_(2″)), R_(2″) ishydrogen, n is 0, and R_(2′) is an alkyl substituted by(CR₁₀R₂₀)_(n)NR_(e)R_(e′). In a further embodiment, R_(e) and R_(e′) areindependently selected from an optionally substituted C₁₋₄ alkyl, suchas methyl, ethyl, isopropyl, n-butyl, or t-butyl, preferably ethyl.

Another embodiment of the invention is the genus of compounds of formula(Ic), a subgenus of compounds of Formula (I) and (Ia) wherein R₁ isC(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), and R_(b) is an optionally substitutedheteroaryl, an optionally substituted heteroaryl C₁₋₁₀ alkyl, anoptionally substituted heterocyclic or an optionally substitutedheterocyclic C₁₋₁₀ alkyl. The remaining groups are the same asenumerated above for Formula (I) and (Ia).

In another embodiment for compounds of Formula (Ic), R₁ isC(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), and R_(b) is an optionally substitutedheteroaryl, or an optionally substituted heteroaryl C₁₋₁₀ alkyl.

Suitably, the heteroaryl, heteroarylalkyl, heterocyclic andheterocyclicalkyl moieties are as defined above for Formula (I) and(Ia). A preferred heteroaryl ring is an optionally substituted thiazolylring, pyridyl, or thiophene ring.

In one embodiment of this invention, for compounds of Formula (I), (Ia),and (Ic), as well as the remaining formulas herein, R_(1′) isindependently selected hydrogen, halogen, C₁₋₄ alkyl, orhalo-substituted-C₁₋₄ alkyl. In another embodiment, R_(1′) isindependently selected from hydrogen, fluorine, chlorine, methyl, orCF₃. In one embodiment when R_(1′) is substituted on the phenyl ring inthe ortho position, and a second R_(1′) moiety is also substituted onthe ring, then preferably the second substitution is not in the otherortho position.

In one embodiment of the invention, g is 1 or 2.

Suitably, in one embodiment when R₃ is an aryl moiety, it is a phenylring, and the phenyl ring is optionally substituted, independently ateach occurrence, one or more times, suitably 1 to 4 times by halogen,C₁₋₄ alkyl, or halo-substituted-C₁₋₄ alkyl. The phenyl ring may suitablybe substituted in the 2, 4, or 6-position, or di-substituted in the2,4-position, such as 2-fluoro, 4-fluoro, 2,4-difluoro, 2,6-difluoro,6-difluoro, or 2-methyl-4-fluoro; or tri-substituted in the2,4,6-position, such as 2,4,6-trifluoro. Preferably, R₃ is a2,6-difluoro phenyl.

In one embodiment, R₃ is a 2,6-difluoro phenyl, R_(1′) is independentlyselected at each occurrence from hydrogen, fluorine, or methyl; g is 1or 2.

In another embodiment of the present invention, for compound ofFormula(s) (I) and (Ia), (II) and (IIa), (III) and (IIIa), (IV) and(IVa), (V) and (Va), (VI) and (VIa-VIi), (VIII) and (VIIIa), (A), (A1),(B) and (B1) the X term may also be the B-Non-Ar-cyc moiety as disclosedin U.S. Pat. No. 6,809,199 whose disclosure is incorporated by referenceherein.

As represented by the disclosure in U.S. Pat. No. 6,809,199, Non-Ar-Cycis suitably selected from:

wherein

d is an integer having a value of 1, 2, 3, or 4;

d′ is 0, or an integer having a value of 1, 2, or 3;

d″ is 0, or an integer having a value of 1, 2, or 3;

e is 0, or is an integer having a value of 1, 2, 3, or 4;

e′ is 0, or an integer having a value of 1, 2, or 3;

e″ is 0, or an integer having a value of 1, 2, or 3;

f is 0, or is an integer having a value of 1, 2, or 3;

d+e is 2, 3, 4, 5, or 6;

d′+e″=d

e′+e″=m

Suitably, R_(7′), R₇₇ and R_(77″) are each independently selected fromhydrogen, C₁₋₆ alkyl-group, C₂₋₆ alkenyl-group, C₄₋₆ cycloalkyl-C₀₋₆alkyl-group, N(C₀₋₄ alkyl)(C₀₋₄ alkyl)-C1-4 alkyl-N(C₀₋₄ alkyl)-group,—N(C₀₋₄ alkyl)(C₀₋₄ alkyl) group, C₁₋₃ alkyl-CO—C₀₋₄ alkyl-group, C₀₋₆alkyl-O—C(O)–C₀₋₄ alkyl-group, C₀₋₆ alkyl-C(O)—O—C₀₋₄alkyl-group, N(C₀₋₄alkyl)(C₀₋₄ alkyl)-(C₀₋₄ alkyl)C(O)(C₀₋₄ alkyl)-group, phenyl-C₀₋₄alkyl-group, pyridyl-C₀₋₄ alkyl-group, pyrimidinyl-C₀₋₄ alkyl-group,pyrazinyl-C₀₋₄ alkyl-group, thiophenyl-C₀₋₄ alkyl-group, pyrazolyl-C₀₋₄alkyl-group, imidazolyl-C₀₋₄ alkyl-group, triazolyl-C₀₋₄ alkyl-group,azetidinyl-C₀₋₄ alkyl-group, pyrrolidinyl-C₀₋₄ alkyl-group,isoquinolinyl-C₀₋₄alkyl-group, indanyl-C₀₋₄ alkyl-group,benzothiazolyl-C₀₋₄ alkyl-group, any of the groups optionallysubstituted with 1-6 substituents, each substituent independently being—OH, —N(C₀₋₄ alkyl)(C₀₋₄alkyl), C₁₋₄alkyl , C₁₋₆ alkoxyl, C₁₋₆alkyl-CO—C₀₋₄ alkyl-, pyrrolidinyl-C₀₋₄ alkyl-, or halogen; or R_(7′)together with a bond from an absent ring hydrogen is ═O.

Suitably, B is —C₁₋₆alkyl-, —C₀₋₃ alkyl-O—C₀₋₃alkyl-, —C₀₋₃alkyl-NH—C₀₋₃alkyl-, —C₀₋₃alkyl-NH—C₃₋₇cycloalkyl-,—C₀₋₃alkyl-N(C₀₋₃alkyl)-C(O)—C₀₋₃ alkyl-, —C₀₋₃ alkyl-NH—SO₂—C₀₋₃alkyl-, —C₀₋₃ alkyl-, —C₀₋₃alkyl-S—C₀₋₃ alkyl-, —C₀₋₃alkyl-SO₂—C₀₋₃alkyl-, —C₀₋₃alkyl-PH—C₀₋₃ alkyl-, C₀₋₃ alkyl —C(O)—C₀₋₃alkyl, or a direct bond.

Suitably, E₁ is CH, N, or CR₆₆; or B and E₁ together form a double bond,i.e., —CH═C.

Suitably, E₂ is CH₂, CHR₇₇, C(OH)R₇₇NH, NR₇₇, O, S, —S(O)—, or —S(O)₂—.

Suitably, R₆₆ is independently selected from at each occurrence fromhalogen, C₀₋₄ alkyl, —C(O)—O (C₀₋₄ alkyl), or —C(O)—N(C₀₋₄ alkyl)-(C₀₋₄alkyl).

In an alternative embodiment of this invention, Non-Ar-Cyc is:

In another embodiment of the present invention, for compound ofFormula(s) (I) and (Ia), (II) and (IIa), (III) and (IIIa), (IV) and(IVa), (V) and (Va), (VI) and (VIa-VIi), (VIII) and (VIIIa), (A), (A1),(B) and (B1) the X term may also be the X moiety as disclosed in WO2004/073628, published September 2004, Boehm et al., whose disclosure isincorporated by reference herein.

In another embodiment of the present invention, compounds of Formula(II) and (IIa) are represented by the structures:

wherein

-   G₁, and G₂ are independently nitrogen;-   G₃ is NH;-   G₄ is nitrogen;-   R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b,)    N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);    N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); or    N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b);-   R_(1′) is independently selected at each occurence from halogen,    C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,    (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅,    S(O)₂R_(5,) or (CR₁₀R₂₀)_(v′)OR₁₃;-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or heterocyclylC₁₋₁₀ alkyl    moiety, which moieties excluding hydrogen, may all be optionally    substituted;-   X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′), (CH₂)_(n′)N(R_(10′))C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or    -   R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    -   (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein each of these moieties, excluding hydrogen, may be    optionally substituted;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein these moieties, excluding hydrogen, may be optionally    substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀ alkyl, or a heterocyclylC₁₋₁₀    alkyl moiety, and wherein each of these moieties may be optionally    substituted;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, and wherein each of    these moieties, excluding hydrogen, may be optionally substituted;    or the R₄ and R₁₄ together with the nitrogen which they are attached    form an optionally substituted heterocyclic ring of 4 to 7 members,    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or nitrogen;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′)    together with the nitrogen to which they are attached form a    heterocyclic ring of 5 to 7 members, which ring optionally contains    an additional heteroatom selected from NR_(9′);-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′,) S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R₁₀′ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R_(d) and R_(d′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylC₁₋₄alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted; or R_(d) and R_(d′) together with the    nitrogen which they are attached form an optionally substituted    heterocyclic ring of 5 to 6 members, which ring optionally contains    an additional heteroatom selected from oxygen, sulfur or NR_(9′);-   g is 0 or an integer having a value of 1, 2, 3, or 4;-   n′ is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6;-   t is an integer having a value of 2 to 6;-   v is 0 or an integer having a value of 1 or 2;-   v′ is 0 or an integer having a value of 1 or 2;-   Z is independently selected at each occurrence from oxygen or    sulfur; and-   a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

Representative examples of compounds of Formula (II) and (IIa) are:

-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-1,3-thiazol-2-ylbenzamide-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic    acid-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(1-methylethyl)benzamide-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-propylbenzamide-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-phenylbenzamide-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)benzamide-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,N-dimethylbenzamide-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-methylbenzamide-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzamide-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methyl-N-(1-methylethyl)benzamide-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methylbenzoic    acid-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methyl-N-propylbenzamide-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methyl-N-phenylbenzamide-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-3-methylbenzamide-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,N,3-trimethylbenzamide-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,3-dimethylbenzamide-   4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methylbenzamide;    or-   a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

Another aspect of the invention are compounds Formula (III) and (IIIa):

wherein

-   G₁, and G₂ are independently nitrogen;-   G₃ is NH;-   G₄ is nitrogen;-   G₅ and G₆ are independently selected from nitrogen or CH;-   R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b,)    N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);    N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); or    N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b);-   R_(1′) is independently selected at each occurence from halogen,    C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,    (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅,    S(O)₂R_(5,) or (CR₁₀R₂₀)_(v′)OR₁₃;-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or heterocyclylC₁₋₁₀ alkyl    moiety, which moieties excluding hydrogen, may all be optionally    substituted;-   X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′), (CH₂)_(n′)N(R_(10′))C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or    -   R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    -   (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein each of these moieties, excluding hydrogen, may be    optionally substituted;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein these moieties, excluding hydrogen, may be optionally    substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀ alkyl, or a heterocyclylC₁₋₁₀    alkyl moiety, and wherein each of these moieties may be optionally    substituted;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, and wherein each of    these moieties, excluding hydrogen, may be optionally substituted;    or the R₄ and R₁₄ together with the nitrogen which they are attached    form an optionally substituted heterocyclic ring of 4 to 7 members,    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or nitrogen;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′)    together with the nitrogen to which they are attached form a    heterocyclic ring of 5 to 7 members, which ring optionally contains    an additional heteroatom selected from NR_(9′);-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′,) S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R₁₀′ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R_(d) and R_(d′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylC₁₋₄alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted; or R_(d) and R_(d′) together with the    nitrogen which they are attached form an optionally substituted    heterocyclic ring of 5 to 6 members, which ring optionally contains    an additional heteroatom selected from oxygen, sulfur or NR_(9′);-   g is 0 or an integer having a value of 1, 2, 3, or 4;-   n′ is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6;-   t is an integer having a value of 2 to 6;-   v is 0 or an integer having a value of 1 or 2;-   v′ is 0 or an integer having a value of 1 or 2;-   Z is independently selected at each occurrence from oxygen or    sulfur; and-   a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

It should be recognized that the difference between compounds of Formula(I) and (Ia), and Formula (II) and (IIa) and those of Formulas (III) and(IIIa) through Formula (V) and (Va) lie not only in the in the ringsubstitution of the R1 group, but that the ring position of the nitrogenin the pyridyl ring. All of the remaining variables have the samemeaning for Formulas (III) and (IIIa) through Formula (V) and (Va) asthose described herein for Formula (I) and (Ia), etc.

Another aspect of the invention are compounds of Formula (IV) and (IVa):

-   G₁, and G₂ are independently nitrogen;-   G₃ is NH;-   G₄ is nitrogen;-   G₅ and G₆ are independently selected from nitrogen or CH;-   R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b,)    N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);    N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); or    N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b);-   R_(1′) is independently selected at each occurence from halogen,    C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,    (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅,    S(O)₂R_(5,) or (CR₁₀R₂₀)_(v′)OR₁₃;-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or heterocyclylC₁₋₁₀ alkyl    moiety, which moieties excluding hydrogen, may all be optionally    substituted;-   X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′), (CH₂)_(n′)N(R_(10′))C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or    -   R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    -   (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein each of these moieties, excluding hydrogen, may be    optionally substituted;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein these moieties, excluding hydrogen, may be optionally    substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀ alkyl, or a heterocyclylC₁₋₁₀    alkyl moiety, and wherein each of these moieties may be optionally    substituted;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, and wherein each of    these moieties, excluding hydrogen, may be optionally substituted;    or the R₄ and R₁₄ together with the nitrogen which they are attached    form an optionally substituted heterocyclic ring of 4 to 7 members,    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or nitrogen;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′)    together with the nitrogen to which they are attached form a    heterocyclic ring of 5 to 7 members, which ring optionally contains    an additional heteroatom selected from NR_(9′);-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′,) S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R₁₀′ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R_(d) and R_(d′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylC₁₋₄alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted; or R_(d) and R_(d′) together with the    nitrogen which they are attached form an optionally substituted    heterocyclic ring of 5 to 6 members, which ring optionally contains    an additional heteroatom selected from oxygen, sulfur or NR_(9′);-   g is 0 or an integer having a value of 1, 2, 3, or 4;-   n′ is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6;-   t is an integer having a value of 2 to 6;-   v is 0 or an integer having a value of 1 or 2;-   v′ is 0 or an integer having a value of 1 or 2;-   Z is independently selected at each occurrence from oxygen or    sulfur; and-   a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

Another aspect of the invention are compounds Formula (V) and (Va):

wherein

-   G₁, and G₂ are independently nitrogen;-   G₃ is NH;-   G₄ is nitrogen;-   G₅ and G₆ are nitrogen and CH, provided that only one of G5 or G6 is    nitrogen and the other is CH;-   R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b,)    N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);    N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); or    N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b);-   R_(1′) is independently selected at each occurence from halogen,    C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,    (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅,    S(O)₂R_(5,) or (CR₁₀R₂₀)_(v′)OR₁₃;-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or heterocyclylC₁₋₁₀ alkyl    moiety, which moieties excluding hydrogen, may all be optionally    substituted;-   X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′), (CH₂)_(n′)N(R_(10′))C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or    -   R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    -   (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein each of these moieties, excluding hydrogen, may be    optionally substituted;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein these moieties, excluding hydrogen, may be optionally    substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀ alkyl, or a heterocyclylC₁₋₁₀    alkyl moiety, and wherein each of these moieties may be optionally    substituted;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, and wherein each of    these moieties, excluding hydrogen, may be optionally substituted;    or the R₄ and R₁₄ together with the nitrogen which they are attached    form an optionally substituted heterocyclic ring of 4 to 7 members,    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or nitrogen;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′)    together with the nitrogen to which they are attached form a    heterocyclic ring of 5 to 7 members, which ring optionally contains    an additional heteroatom selected from NR_(9′);-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′,) S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R₁₀′ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R_(d) and R_(d′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylC₁₋₄alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted; or R_(d) and R_(d′) together with the    nitrogen which they are attached form an optionally substituted    heterocyclic ring of 5 to 6 members, which ring optionally contains    an additional heteroatom selected from oxygen, sulfur or NR_(9′);-   g is 0 or an integer having a value of 1, 2, 3, or 4;-   n′ is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6;-   t is an integer having a value of 2 to 6;-   v is 0 or an integer having a value of 1 or 2;-   v′ is 0 or an integer having a value of 1 or 2;-   Z is independently selected at each occurrence from oxygen or    sulfur; and-   a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

Another aspect of the invention are compounds formula (VI) and (VIa):

wherein

-   G₁, and G₂ are independently nitrogen;-   G₃ is NH;-   G₄ is nitrogen;-   one of G₅, G₆, G₇ and G₈ is nitrogen and the others are CH;-   R₁ is C(Z)N(R10′)(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b,)    N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);    N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); or    N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b);-   R_(1′) is independently selected at each occurence from halogen,    C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,    (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅,    S(O)₂R_(5,) or (CR₁₀R₂₀)_(v′)OR₁₃;-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or heterocyclylC₁₋₁₀ alkyl    moiety, which moieties excluding hydrogen, may all be optionally    substituted;-   X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′), (CH₂)_(n′)N(R_(10′))C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or    -   R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    -   (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein each of these moieties, excluding hydrogen, may be    optionally substituted;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein these moieties, excluding hydrogen, may be optionally    substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀ alkyl, or a heterocyclylC₁₋₁₀    alkyl moiety, and wherein each of these moieties may be optionally    substituted;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, and wherein each of    these moieties, excluding hydrogen, may be optionally substituted;    or the R₄ and R₁₄ together with the nitrogen which they are attached    form an optionally substituted heterocyclic ring of 4 to 7 members,    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or nitrogen;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′)    together with the nitrogen to which they are attached form a    heterocyclic ring of 5 to 7 members, which ring optionally contains    an additional heteroatom selected from NR_(9′);-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′,) S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R₁₀′ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R_(d) and R_(d′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylC₁₋₄alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted; or R_(d) and R_(d′) together with the    nitrogen which they are attached form an optionally substituted    heterocyclic ring of 5 to 6 members, which ring optionally contains    an additional heteroatom selected from oxygen, sulfur or NR_(9′);-   g is 0 or an integer having a value of 1, 2, 3, or 4;-   n′ is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6;-   t is an integer having a value of 2 to 6;-   v is 0 or an integer having a value of 1 or 2;-   v′ is 0 or an integer having a value of 1 or 2;-   Z is independently selected at each occurrence from oxygen or    sulfur; and-   a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

It should be recognized that the difference between compounds of Formula(I) and (Ia), and Formula (II) and (IIa) and those of Formulas (VII)through Formula (VIi) lie not only in the in the ring substitution ofthe R1 group, but that the ring position of the two nitrogen's in thepyrimidine ring. All of the remaining variables have the same meaningfor Formulas (VI) through Formula (VIi) as those described herein forFormula (I) and (Ia), etc.

Another aspect of the invention are compounds of Formula (VIb) and(VIc):

wherein

-   G₁, and G₂ are independently nitrogen;-   G₃ is NH;-   G₄ is nitrogen;-   G₅ and G₆ are nitrogen; and-   G₇ and G₈ are CH;-   R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b,)    N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);    N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); or    N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b);-   R_(1′) is independently selected at each occurence from halogen,    C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,    (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅,    S(O)₂R_(5,) or (CR₁₀R₂₀)_(v′)OR₁₃;-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or heterocyclylC₁₋₁₀ alkyl    moiety, which moieties excluding hydrogen, may all be optionally    substituted;-   X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′), (CH₂)_(n′)N(R_(10′))C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or    -   R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    -   (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein each of these moieties, excluding hydrogen, may be    optionally substituted;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein these moieties, excluding hydrogen, may be optionally    substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀ alkyl, or a heterocyclylC₁₋₁₀    alkyl moiety, and wherein each of these moieties may be optionally    substituted;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, and wherein each of    these moieties, excluding hydrogen, may be optionally substituted;    or the R₄ and R₁₄ together with the nitrogen which they are attached    form an optionally substituted heterocyclic ring of 4 to 7 members,    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or nitrogen;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′)    together with the nitrogen to which they are attached form a    heterocyclic ring of 5 to 7 members, which ring optionally contains    an additional heteroatom selected from NR_(9′);-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′,) S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R₁₀′ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R_(d) and R_(d′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylC₁₋₄alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted; or R_(d) and R_(d′) together with the    nitrogen which they are attached form an optionally substituted    heterocyclic ring of 5 to 6 members, which ring optionally contains    an additional heteroatom selected from oxygen, sulfur or NR_(9′);-   g is 0 or an integer having a value of 1, 2, 3, or 4;-   n′ is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6;-   t is an integer having a value of 2 to 6;-   v is 0 or an integer having a value of 1 or 2;-   v′ is 0 or an integer having a value of 1 or 2;-   Z is independently selected at each occurrence from oxygen or    sulfur; and-   a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

Another aspect of the invention are compounds Formula (VId) and (VIe):

wherein

-   G₁, and G₂ are independently nitrogen;-   G₃ is NH;-   G₄ is nitrogen;-   G₆ and G₈ are nitrogen;-   G₅ and G₇ are CH;-   R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b,)    N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);    N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); or    N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b);-   R_(1′) is independently selected at each occurence from halogen,    C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,    (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅,    S(O)₂R_(5,) or (CR₁₀R₂₀)_(v′)OR₁₃;-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or heterocyclylC₁₋₁₀ alkyl    moiety, which moieties excluding hydrogen, may all be optionally    substituted;-   X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′), (CH₂)_(n′)N(R_(10′))C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or    -   R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    -   (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein each of these moieties, excluding hydrogen, may be    optionally substituted;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein these moieties, excluding hydrogen, may be optionally    substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀ alkyl, or a heterocyclylC₁₋₁₀    alkyl moiety, and wherein each of these moieties may be optionally    substituted;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, and wherein each of    these moieties, excluding hydrogen, may be optionally substituted;    or the R₄ and R₁₄ together with the nitrogen which they are attached    form an optionally substituted heterocyclic ring of 4 to 7 members,    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or nitrogen;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′)    together with the nitrogen to which they are attached form a    heterocyclic ring of 5 to 7 members, which ring optionally contains    an additional heteroatom selected from NR_(9′);-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′,) S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R₁₀′ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R_(d) and R_(d′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylC₁₋₄alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted; or R_(d) and R_(d′) together with the    nitrogen which they are attached form an optionally substituted    heterocyclic ring of 5 to 6 members, which ring optionally contains    an additional heteroatom selected from oxygen, sulfur or NR_(9′);-   g is 0 or an integer having a value of 1, 2, 3, or 4;-   n′ is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6;-   t is an integer having a value of 2 to 6;-   v is 0 or an integer having a value of 1 or 2;-   v′ is 0 or an integer having a value of 1 or 2;-   Z is independently selected at each occurrence from oxygen or    sulfur; and-   a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

Another aspect of the invention are compounds Formula (VIf) and (VIg):

wherein

-   G₁, and G₂ are independently nitrogen;-   G₃ is NH;-   G₄ is nitrogen;-   G₅ and G₈ are nitrogen;-   G₆ and G₇ are CH;-   R₁ is C(Z)N(R_(10′)′)(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b,)    N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);    N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); or    N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b);-   R_(1′) is independently selected at each occurence from halogen,    C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,    (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅,    S(O)₂R_(5,) or (CR₁₀R₂₀)_(v′)OR₁₃;-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or heterocyclylC₁₋₁₀ alkyl    moiety, which moieties excluding hydrogen, may all be optionally    substituted;-   X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′), (CH₂)_(n′)N(R_(10′))C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or    -   R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    -   (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein each of these moieties, excluding hydrogen, may be    optionally substituted;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein these moieties, excluding hydrogen, may be optionally    substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀ alkyl, or a heterocyclylC₁₋₁₀    alkyl moiety, and wherein each of these moieties may be optionally    substituted;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, and wherein each of    these moieties, excluding hydrogen, may be optionally substituted;    or the R₄ and R₁₄ together with the nitrogen which they are attached    form an optionally substituted heterocyclic ring of 4 to 7 members,    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or nitrogen;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′)    together with the nitrogen to which they are attached form a    heterocyclic ring of 5 to 7 members, which ring optionally contains    an additional heteroatom selected from NR_(9′);-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′,) S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R₁₀′ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R_(d) and R_(d′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylC₁₋₄alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted; or R_(d) and R_(d′) together with the    nitrogen which they are attached form an optionally substituted    heterocyclic ring of 5 to 6 members, which ring optionally contains    an additional heteroatom selected from oxygen, sulfur or NR_(9′);-   g is 0 or an integer having a value of 1, 2, 3, or 4;-   n′ is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6;-   t is an integer having a value of 2 to 6;-   v is 0 or an integer having a value of 1 or 2;-   v′ is 0 or an integer having a value of 1 or 2;-   Z is independently selected at each occurrence from oxygen or    sulfur; and-   a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

Another aspect of the invention are compounds of the formula (VIh) and(VIi):

wherein

-   G₁, and G₂ are independently nitrogen;-   G₃ is NH;-   G₄ is nitrogen;-   G₆ and G₇ are nitrogen;-   G₅ and G₈ are CH;-   R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b,)    N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);    N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); or    N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b);-   R_(1′) is independently selected at each occurence from halogen,    C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,    (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅,    S(O)₂R_(5,) or (CR₁₀R₂₀)_(v′)OR₁₃;-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or heterocyclylC₁₋₁₀ alkyl    moiety, which moieties excluding hydrogen, may all be optionally    substituted;-   X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′), (CH₂)_(n′)N(R_(10′))C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or    -   R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    -   (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein each of these moieties, excluding hydrogen, may be    optionally substituted;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein these moieties, excluding hydrogen, may be optionally    substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀ alkyl, or a heterocyclylC₁₋₁₀    alkyl moiety, and wherein each of these moieties may be optionally    substituted;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, and wherein each of    these moieties, excluding hydrogen, may be optionally substituted;    or the R₄ and R₁₄ together with the nitrogen which they are attached    form an optionally substituted heterocyclic ring of 4 to 7 members,    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or nitrogen;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′)    together with the nitrogen to which they are attached form a    heterocyclic ring of 5 to 7 members, which ring optionally contains    an additional heteroatom selected from NR_(9′);-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′,) S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R₁₀′ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R_(d) and R_(d′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylC₁₋₄alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted; or R_(d) and R_(d′) together with the    nitrogen which they are attached form an optionally substituted    heterocyclic ring of 5 to 6 members, which ring optionally contains    an additional heteroatom selected from oxygen, sulfur or NR_(9′);-   g is 0 or an integer having a value of 1, 2, 3, or 4;-   n′ is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6;-   t is an integer having a value of 2 to 6;-   v is 0 or an integer having a value of 1 or 2;-   v′ is 0 or an integer having a value of 1 or 2;-   Z is independently selected at each occurrence from oxygen or    sulfur; and-   a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

Another aspect of the invention are compounds of Formula (A) and (A1):

wherein

-   G₁, and G₂ are independently nitrogen;-   G₃ is NH;-   G₄ is nitrogen;-   Y is C(R_(x))(R_(z)), C(O), N(R_(z)), N(R_(w))C(R_(y))(R_(z)),    oxygen, OC(R_(y))(R_(z)), S(O)m, or S(O)_(m)C(R_(y))(R_(z));-   R_(x) is hydrogen, C₁₋₂ alkyl, N(R_(v))₂, hydroxy, thio, C₁₋₂    alkoxy, or S(O)_(m)C₁₋₂ alkyl;-   R_(y) is hydrogen or C₁₋₂ alkyl;-   R_(z) is hydrogen or C₁₋₂ alkyl;-   R_(w), is hydrogen or C₁₋₂ alkyl;-   R_(v) is independently selected from hydrogen or C₁₋₂ alkyl;-   R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b,)    N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);    N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); or    N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b);-   R_(1′) is independently selected at each occurence from halogen,    C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,    (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅,    S(O)₂R_(5,) or (CR₁₀R₂₀)_(v′)OR₁₃;-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or heterocyclylC₁₋₁₀ alkyl    moiety, which moieties excluding hydrogen, may all be optionally    substituted;-   X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′), (CH₂)_(n′)N(R_(10′))C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or    -   R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    -   (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein each of these moieties, excluding hydrogen, may be    optionally substituted;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein these moieties, excluding hydrogen, may be optionally    substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀ alkyl, or a heterocyclylC₁₋₁₀    alkyl moiety, and wherein each of these moieties may be optionally    substituted;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, and wherein each of    these moieties, excluding hydrogen, may be optionally substituted;    or the R₄ and R₁₄ together with the nitrogen which they are attached    form an optionally substituted heterocyclic ring of 4 to 7 members,    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or nitrogen;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′)    together with the nitrogen to which they are attached form a    heterocyclic ring of 5 to 7 members, which ring optionally contains    an additional heteroatom selected from NR_(9′);-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′,) S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R₁₀′ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R_(d) and R_(d′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylC₁₋₄alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted; or R_(d) and R_(d′) together with the    nitrogen which they are attached form an optionally substituted    heterocyclic ring of 5 to 6 members, which ring optionally contains    an additional heteroatom selected from oxygen, sulfur or NR_(9′);-   g is 0 or an integer having a value of 1, 2, 3, or 4;-   n′ is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6;-   t is an integer having a value of 2 to 6;-   v is 0 or an integer having a value of 1 or 2;-   v′ is 0 or an integer having a value of 1 or 2;-   Z is independently selected at each occurrence from oxygen or    sulfur; and-   a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

The present invention is directed to novel compounds of Formula (A) andFormula (A1), or a pharmaceutically acceptable derivative thereof. Aswill be readily recognized, the difference between compounds of Formula(A) and Formula (A1), and that of Formula (I) and (Ia) lies in thelinker Y. The respective R₁, R₂, and R₃, etc. terms are the same forboth groups. For purposes herein, everything applicable to Formula (I)is also applicable to Formula (A) unless otherwise indicated.

Another aspect of the invention are compounds of Formulas (B) and (B1):

wherein

-   G₁, and G₂ are independently nitrogen;-   G₃ is NH;-   G₄ is nitrogen;-   Y is C(R_(x))(R_(z)), C(O), N(R_(z)), N(R_(w))C(R_(y))(R_(z)),    oxygen, OC(R_(y))(R_(z)), S(O)m, or S(O)_(m)C(R_(y))(R_(z));-   R_(x) is hydrogen, C₁₋₂ alkyl, N(R_(v))₂, hydroxy, thio, C₁₋₂    alkoxy, or S(O)_(m)C₁₋₂ alkyl;-   R_(y) is hydrogen or C₁₋₂ alkyl;-   R_(z) is hydrogen or C₁₋₂ alkyl;-   R_(w), is hydrogen or C₁₋₂ alkyl;-   R_(v) is independently selected at each occurrence from hydrogen or    C₁₋₂ alkyl;-   R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b,)    N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);    N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); or    N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b);-   R_(1′) is independently selected at each occurence from halogen,    C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,    (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅,    S(O)₂R_(5,) or (CR₁₀R₂₀)_(v′)OR₁₃;-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or heterocyclylC₁₋₁₀ alkyl    moiety, which moieties excluding hydrogen, may all be optionally    substituted;-   X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′), (CH₂)_(n′)N(R_(10′))C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or    -   R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    -   (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein each of these moieties, excluding hydrogen, may be    optionally substituted;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein these moieties, excluding hydrogen, may be optionally    substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀ alkyl, or a heterocyclylC₁₋₁₀    alkyl moiety, and wherein each of these moieties may be optionally    substituted;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, and wherein each of    these moieties, excluding hydrogen, may be optionally substituted;    or the R₄ and R₁₄ together with the nitrogen which they are attached    form an optionally substituted heterocyclic ring of 4 to 7 members,    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or nitrogen;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′)    together with the nitrogen to which they are attached form a    heterocyclic ring of 5 to 7 members, which ring optionally contains    an additional heteroatom selected from NR_(9′);-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′,) S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R₁₀′ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R_(d) and R_(d′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylC₁₋₄alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted; or R_(d) and R_(d′) together with the    nitrogen which they are attached form an optionally substituted    heterocyclic ring of 5 to 6 members, which ring optionally contains    an additional heteroatom selected from oxygen, sulfur or NR_(9′);-   g is 0 or an integer having a value of 1, 2, 3, or 4;-   n′ is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6;-   t is an integer having a value of 2 to 6;-   v is 0 or an integer having a value of 1 or 2;-   v′ is 0 or an integer having a value of 1 or 2;-   Z is independently selected at each occurrence from oxygen or    sulfur; and-   a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

As will be readily recognized, the differences between compounds ofFormula (B) and Formula (B1), and that of Formula (II) and (IIa) lie inthe linker Y. The respective R₁, R₂, and R₃, etc. terms are the same forboth groups. For purposes herein, everything applicable to Formula (II)is also applicable to Formula (B) unless otherwise indicated.

In another aspect of the invention, it is the linker Y may be present ina similar manner in the same position for all of the remaining formulas,Formula's (III) and (IIIa), (IV) and (IVa), (V) and (Va), (VI) and(VIa-VIi), herein. The respective R₁, R₂, and R₃, etc. terms will be thesame for all the groups.

Another aspect of the invention are compounds of Formula (VIII) and(VIIIa):

wherein

-   G₁, G₂ are independently nitrogen or CH, but G₁, and G₂ are not both    nitrogen;-   G₃ is NH;-   G₄ is nitrogen;-   R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b,)    N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);    N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); or    N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b);-   R_(1′) is independently selected at each occurence from halogen,    C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,    (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅,    S(O)₂R_(5,) or (CR₁₀R₂₀)_(v′)OR₁₃;-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or heterocyclylC₁₋₁₀ alkyl    moiety, which moieties excluding hydrogen, may all be optionally    substituted;-   X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′), (CH₂)_(n′)N(R_(10′))C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or    -   R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    -   (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein each of these moieties, excluding hydrogen, may be    optionally substituted;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein these moieties, excluding hydrogen, may be optionally    substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀ alkyl, or a heterocyclylC₁₋₁₀    alkyl moiety, and wherein each of these moieties may be optionally    substituted;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, and wherein each of    these moieties, excluding hydrogen, may be optionally substituted;    or the R₄ and R₁₄ together with the nitrogen which they are attached    form an optionally substituted heterocyclic ring of 4 to 7 members,    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or nitrogen;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′)    together with the nitrogen to which they are attached form a    heterocyclic ring of 5 to 7 members, which ring optionally contains    an additional heteroatom selected from NR_(9′);-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′,) S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R₁₀′ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R_(d) and R_(d′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylC₁₋₄alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted; or R_(d) and R_(d′) together with the    nitrogen which they are attached form an optionally substituted    heterocyclic ring of 5 to 6 members, which ring optionally contains    an additional heteroatom selected from oxygen, sulfur or NR_(9′);-   g is 0 or an integer having a value of 1, 2, 3, or 4;-   n′ is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6;-   t is an integer having a value of 2 to 6;-   v is 0 or an integer having a value of 1 or 2;-   v′ is 0 or an integer having a value of 1 or 2;-   Z is independently selected at each occurrence from oxygen or    sulfur; and-   a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

In another embodiment of the present invention, for compounds of Formula(VIII) and (VIIIa), and any of the other remaining formulas, the X termmay also be the B-Non-Ar-cyc moiety as disclosed above.

In another embodiment of the present invention, for compound of Formula(VIII) and (VIIIa), and any of the other remaining formulas, the X termmay also be the X moiety as disclosed in WO 2004/073628, publishedSeptember 2004, Boehm et al., whose disclosure is incorporated byreference herein.

For purposes herein the template containing the G₁ and G₂ moieties willhave a numbering system that allows for different (R₁ and R_(1′))substituents on the phenyl or pyridyl or pyrimidine ring at the C₄position; the X term at the C₂ position, and at the R₃ substituent inthe N₈ position.

The respective R₁, R₂, R_(x), X and R₃, etc., terms are the same forboth groups within the formulas themselves, for instance, in Formula(VIII) and (VIIIa). For purposes herein, everything applicable toFormula (VIII) is also applicable to Formula (VIIIa) unless otherwiseindicated.

It is recognized that for compounds of Formula (I) and (Ia), etc. andthose of Formula (VIII) and (VIIIa) the difference is in the allowanceof the G₁ and G₂ moieties to be carbon or nitrogen, independently. Forpurposes of brevity herein, the remaining compounds of Formulas (II) and(IIa), (III) and (IIIa), (IV) and (IVa), (V) and (Va), (VI) and(VIa-VIi), may also have the same pharmacophore template of:

Illustrative of this would be the C4 substitution from compounds offormula (II) and (IIa) on this pharmacophore template, represented bythe structure:

wherein

-   G₁, and G₂ are independently nitrogen or CH, but G₁, and G₂ are not    both nitrogen;-   G₃ is NH;-   G₄ is nitrogen;-   R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b,)    N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);    N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); or    N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b);-   R_(1′) is independently selected at each occurence from halogen,    C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,    (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅,    S(O)₂R_(5,) or (CR₁₀R₂₀)_(v′)OR₁₃;-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or heterocyclylC₁₋₁₀ alkyl    moiety, which moieties excluding hydrogen, may all be optionally    substituted;-   X is R₂, OR_(2′), S(O)_(m)R_(2′),    (CH₂)_(n′)N(R_(10′))S(O)_(m)R_(2′), (CH₂)_(n′)N(R_(10′))C(O)R_(2′),    (CH₂)_(n′)NR₄R₁₄, (CH₂)_(n′)N(R_(2′))(R_(2″)), or    N(R_(10′))—R_(h)—NH—C(═N—CN)NRqRq′;-   X₁ is N(R₁₁), O, S(O)_(m), or CR₁₀R₂₀;-   R_(h) is selected from an optionally substituted C₁₋₁₀ alkyl,    —CH₂—C(O)—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—C(O)N(R_(10′))CH₂—CH₂—,    —CH₂—N(R_(10′))C(O)CH₂—, —CH₂—CH(OR_(10′))—CH₂, —CH₂—C(O)O—CH₂—CH₂—,    or —CH₂—CH₂—O—C(O)CH₂—;-   R_(q) and R_(q′) are independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,    C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀alkyl, aryl, arylC₁₋₁₀    alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a    heterocyclylC₁₋₁₀ alkyl moiety, wherein all of the moieties,    excluding hydrogen, are optionally substituted, or R_(q) and R_(q′)    together with the nitrogen to which they are attached form a 5 to 7    membered optionally substituted ring, which ring may contain an    additional heteroatom selected from oxygen, nitrogen or sulfur;-   R₂ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties, excluding hydrogen, may be optionally    substituted; or    -   R₂ is the moiety (CR₁₀R₂₀)_(q′)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    -   (CR₁₀R₂₀)_(q′)C(A₁)(A₂)(A₃);-   R_(2′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein each of these moieties, excluding hydrogen, may be    optionally substituted;-   R_(2″) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylalkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀    alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, and    wherein these moieties, excluding hydrogen, may be optionally    substituted; or    -   wherein R_(2″) is the moiety        (CR₁₀R₂₀)_(t)X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃);-   A₁ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl, heterocyclic,    heterocyclic C₁₋₁₀ alkyl, heteroaryl, heteroaryl C₁₋₁₀ alkyl, aryl,    or aryl C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀ alkyl, or a heterocyclylC₁₋₁₀    alkyl moiety, and wherein each of these moieties may be optionally    substituted;-   R₄ and R₁₄ are each independently selected at each occurrence from    hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl,    aryl, aryl-C₁₋₄ alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl,    heteroaryl or a heteroaryl C₁₋₄ alkyl moiety, and wherein each of    these moieties, excluding hydrogen, may be optionally substituted;    or the R₄ and R₁₄ together with the nitrogen which they are attached    form an optionally substituted heterocyclic ring of 4 to 7 members,    which ring optionally contains an additional heteroatom selected    from oxygen, sulfur or nitrogen;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′)    together with the nitrogen to which they are attached form a    heterocyclic ring of 5 to 7 members, which ring optionally contains    an additional heteroatom selected from NR_(9′);-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′,) S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R₁₀′ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₁ is independently selected at each occurrence from hydrogen or    C₁₋₄alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R_(d) and R_(d′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylC₁₋₄alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted; or R_(d) and R_(d′) together with the    nitrogen which they are attached form an optionally substituted    heterocyclic ring of 5 to 6 members, which ring optionally contains    an additional heteroatom selected from oxygen, sulfur or NR_(9′);-   g is 0 or an integer having a value of 1, 2, 3, or 4;-   n′ is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   q′ is 0, or an integer having a value of 1 to 6;-   t is an integer having a value of 2 to 6;-   v is 0 or an integer having a value of 1 or 2;-   v′ is 0 or an integer having a value of 1 or 2;-   Z is independently selected at each occurrence from oxygen or    sulfur; and-   a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

Therefore, compounds having the C4 position substitution from Formula(III) and (IIIa) with the G1/G2 pharmacophore template of carbon ornitrogen, would be considered compounds of Formula (X) and (Xa), etc.

Suitably synthesis to make compounds of Formula (VIII), (IX), (X), etc.,are known to the skilled artisan in this field. Similar processes areprovided for in WO 2004/073628, published September 2004, Boehm et al.,and in U.S. Pat. No. 6,809,199 whose disclosures are incorporated hereinby reference. It is also recognized that in order to have the variety ofdifferent R₁, R₂, X, and R₃ groups, etc. some optional substituents mayneed to be suitably protected to achieve compatibility with thereactions as outlined therein. Subsequent deprotection in those caseswould then afford compounds of the nature generally disclosed.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described hereinabove.It is also to be understood that the present invention encompassescompounds of formula (I) in which a particular group or parameter, forexample R₅, R₆, R₉, R₁₀, R₁₁, R₁₂, R₁₃, p, n, or q, etc. may occur morethan once. In such compounds it will be appreciated that each group orparameter is independently selected from the values listed. When anyvariable occurs more than one time in a Formula (as described herein),its definition on each occurrence is independent of its definition atevery other occurrence.

Particular compounds according to the invention include those mentionedin the examples and their pharmaceutically derivatives.

As used herein, the term “pharmaceutically acceptable” means a compoundwhich is suitable for pharmaceutical and veterinary usage. Salts andsolvates of compounds of the invention which are suitable for use inmedicine are those wherein the counterion or associated solvent ispharmaceutically acceptable. However, salts and solvates havingnon-pharmaceutically acceptable counterions or associated solvents arewithin the scope of the present invention, for example, for use asintermediates in the preparation of other compounds of the invention andtheir pharmaceutically acceptable salts and solvates.

As used herein, the term “pharmaceutically acceptable derivative”, meansany pharmaceutically acceptable salt, solvate or prodrug e.g. ester, ofa compound of the invention, which upon administration to the recipientis capable of providing (directly or indirectly) a compound of theinvention, or an active metabolite or residue thereof. Such derivativesare recognizable to those skilled in the art, without undueexperimentation. Nevertheless, reference is made to the teaching ofBurger's Medicinal Chemistry and Drug Discovery, 5^(th) Edition, Vol. 1:Principles and Practice, which is incorporated herein by reference tothe extent of teaching such derivatives. In one embodimentpharmaceutically acceptable derivatives are salts, solvates, esters,carbamates and phosphate esters. In another embodiment pharmaceuticallyacceptable derivatives are salts, solvates and esters. In yet anotherembodiment of the invention pharmaceutically acceptable derivatives aresalts and esters, in particular salts.

The compounds of the present invention may be in the form of and/or maybe administered as a pharmaceutically acceptable salt. For a review onsuitable salts see Berge et al., J. Pharm. Sci., 1977, 66, 1-19.

Typically, a pharmaceutical acceptable salt may be readily prepared byusing a desired acid or base as appropriate. The salt may precipitatefrom solution and be collected by filtration or may be recovered byevaporation of the solvent.

Salts of the compounds of the present invention may, for example,comprise acid addition salts resulting from reaction of an acid with anitrogen atom present in a compound of formula (I). Salts encompassedwithin the term “pharmaceutically acceptable salts” refer to non-toxicsalts of the compounds of this invention. Suitable addition salts areformed from acids which form non-toxic salts and examples are acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,ethanesulphonate, formate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydrogen phosphate, hydroiodide, hydroxynaphthoate,iodide, isethionate, lactate, lactobionate, laurate, malate, maleate,mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine,oxalate, oxaloacetate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, piruvate, polygalacturonate, saccharate,salicylate, stearate, subacetate, succinate, sulphate, tannate,tartrate, teoclate, tosylate, triethiodide, trifluoroacetate andvalerate.

Pharmaceutically acceptable base salts include ammonium salts such as atrimethylammonium salt, alkali metal salts such as those of sodium andpotassium, alkaline earth metal salts such as those of calcium andmagnesium and salts with organic bases, including salts of primary,secondary and tertiary amines, such as isopropylamine, diethylamine,ethanolamine, trimethylamine, dicyclohexyl amine andN-methyl-D-glucamine.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. As used herein, the term “solvate”refers to a complex of variable stoichiometry formed by a solute (inthis invention, a compound of Formula (I), or a salt thereof) and asolvent. Such solvents for the purpose of the invention may notinterfere with the biological activity of the solute. Examples ofsuitable solvents include water, methanol, ethanol and acetic acid.Preferably the solvent used is a pharmaceutically acceptable solvent.Examples of suitable pharmaceutically acceptable solvents include water,ethanol and acetic acid. Most preferably the solvent used is water. Acomplex with water is known as a “hydrate”. Solvates of the compound ofthe invention are within the scope of the invention.

As used herein, the term “prodrug” means a compound which is convertedwithin the body, e.g. by hydrolysis in the blood, into its active formthat has medical effects. Pharmaceutically acceptable prodrugs aredescribed in T. Higuchi and V. Stella, Prodrugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series; Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987; and in D. Fleisher, S. Ramon andH. Barbra “Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs”, Advanced Drug Delivery Reviews (1996) 19(2)115-130, each of which are incorporated herein by reference.

Prodrugs are any covalently bonded carriers that release a compound offormula (I) in vivo when such prodrug is administered to a patient.Prodrugs are generally prepared by modifying functional groups in a waysuch that the modification is cleaved, either by routine manipulation orin vivo, yielding the parent compound. Prodrugs include, for example,compounds of this invention wherein hydroxy or amine groups are bondedto any group that, when administered to a patient, cleaves to form thehydroxy or amine groups. Thus, representative examples of prodrugsinclude (but are not limited to) acetate, formate and benzoatederivatives of alcohol and amine functional groups of the compounds offormula (I). Further, in the case of a carboxylic acid (—COOH), estersmay be employed, such as methyl esters, ethyl esters, and the like.Esters may be active in their own right and/or be hydrolysable under invivo conditions in the human body. Suitable pharmaceutically acceptablein vivo hydrolysable ester groups include those which break down readilyin the human body to leave the parent acid or its salt.

As used herein, “optionally substituted” unless specifically definedshall mean such groups as halogen, such as fluorine, chlorine, bromineor iodine; hydroxy; hydroxy substituted C₁₋₁₀ alkyl; C₁₋₁₀ alkoxy, suchas methoxy or ethoxy; halosubstituted C₁₋₁₀ alkoxy; S(O)m alkyl, such asmethyl thio, methylsulfinyl or methyl sulfonyl; a ketone (—C(O)), or analdehyde (—C(O)R_(6′)), such as C(O)C₁₋₁₀ alkyl or C(O)aryl, whereinR_(6′) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl (and wherein the R_(6′) moieties, excludinghydrogen, may themselves be optionally substituted 1 or 2 times,independently by halogen; hydroxy; hydroxy substituted alkyl; C₁₋₄alkoxy; S(O)_(m)C₁₋₄ alkyl; amino, mono & di-substituted C₁₋₄ alkylamino; C₁₋₄ alkyl, or CF₃); C(O)OR_(6′); NR_(4′)R_(14′), wherein R_(4′)and R_(14′) are each independently hydrogen or C₁₋₄ alkyl, such as aminoor mono or -disubstituted C₁₋₄ alkyl or wherein the R_(4′)R_(14′) cancyclize together with the nitrogen to which they are attached to form a5 to 7 membered ring which optionally contains an additional heteroatomselected from O/N/S; C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, or C₃₋₇cycloalkylC₁₋₁₀ alkyl group, such as methyl, ethyl, propyl, isopropyl, t-butyl,etc. or cyclopropyl methyl; halosubstituted C₁₋₁₀ alkyl, such CF₂CF₂H,or CF₃; an optionally substituted aryl, such as phenyl, or an optionallysubstituted arylalkyl, such as benzyl or phenethyl, wherein these arylcontaining moieties may also be substituted one to two times by halogen;hydroxy; hydroxy substituted alkyl; C₁₋₄ alkoxy; S(O)_(m) C₁₋₄ alkyl;amino, mono & di-substituted C₁₋₄ alkyl amino; C₁₋₄ alkyl, or CF₃.

Suitable pharmaceutically acceptable salts are well known to thoseskilled in the art and include salts formed with both organic andinorganic acids or bases. Pharmaceutically acceptable acid additionsalts include those formed from hydrochloric, hydrobromic, sulphuric,citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic,triphenylacetic, sulphamic, sulphanilic, succinic, oxalic, fumaric,maleic, malic, glutamic, aspartic, oxaloacetic, alkyl sulphonic acidderivatives, such as methanesulphonic, or ethanesulphonic, arylsulphonicacid derivatives, such as p-toluenesulphonic, m-toluenesulphonic,benzenesulphonic, camphor sulphonic, 4-chlorobenzenesulphonic,4-bromobenzenesulphonic, 4-phenylbenzenesulphonic, naphthalenesulphonicor naphthalenedisulphonic), phenylacetic, mandelic, salicylic, glutaric,gluconic, tricarballylic, cinnamic, substituted cinnamic (for example,phenyl, methyl, cynao, methoxy or halo substituted cinnamic, including4-methyl and 4-methoxycinnamic acid), ascorbic, oleic, naphthoic,hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic),naphthaleneacrylic (for example naphthalene-2-acrylic), benzoic,4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic,4-phenylbenzoic, benzeneacrylic (for example 1,4-benzenediacrylic) andisethionic acids.

Pharmaceutically acceptable base salts include ammonium salts, alkalimetal salts such as those of sodium and potassium, alkaline earth metalsalts such as those of calcium and magnesium and salts with organicbases such as dicyclohexyl amine and N-methyl-D-glucamine.

In addition, pharmaceutically acceptable salts of compounds of Formula(I) may also be formed with a pharmaceutically acceptable cation, forinstance, if a substituent group comprises a carboxy moiety. Suitablepharmaceutically acceptable cations are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium and quaternaryammonium cations.

The term “halo” or “halogens” is used herein to mean the halogens,chloro, fluoro, bromo and iodo.

As used herein, the term “C₁₋₁₀alkyl” or “alkyl” or “alkyl₁₋₁₀” is usedherein to mean both straight and branched hydrocarbon chain containingthe specified number of carbon atoms, e.g. C₁₋₁₀alkyl means a straightof branched alkyl chain of at least 1, and at most 10, carbon atoms,unless the chain length is otherwise limited. Examples of “alkyl” asused herein include, but are not limited to, methyl, ethyl, n-propyl,n-butyl, n-pentyl, isobutyl, isopropyl, sec-butyl, tent-butyl or t-butyland hexyl and the like.

As used herein, the term “alkenyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms andcontaining at least one double bond. For example, C₂₋₆alkenyl means astraight or branched alkenyl containing at least 2, and at most 6,carbon atoms and containing at least one double bond. Examples of“alkenyl” as used herein include, but are not limited to ethenyl,2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl,3-methyl-2-butenyl, 3-methylbut-2-enyl, 3-hexenyl,1,1-dimethylbut-2-enyl and the like.

As used herein, the term “alkoxy” refers to straight or branched chainalkoxy groups containing the specified number of carbon atoms. Forexample, C₁₋₆alkoxy means a straight or branched alkoxy containing atleast 1, and at most 6, carbon atoms. Examples of “alkoxy” as usedherein include, but are not limited to, methoxy, ethoxy, propoxy,prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy,pentoxy and hexyloxy.

As used herein, the term “cycloalkyl” refers to cyclic radicals, such asa non-aromatic hydrocarbon ring containing a specified number of carbonatoms. For example, C₃₋₇cycloalkyl means a non-aromatic ring containingat least three, and at most seven, ring carbon atoms. Representativeexamples of “cycloalkyl” as used herein include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl and thelike.

The term “cycloalkenyl” is used herein to mean cyclic radicals, such asa non-aromatic hydrocarbon ring containing a specified number of carbonatoms preferably of 5 to 7 carbons, which have at least one bondincluding but not limited to cyclopentenyl, cyclohexenyl, and the like.

The term “alkenyl” is used herein at all occurrences to mean straight orbranched chain radical of 2-10 carbon atoms, unless the chain length islimited thereto, including, but not limited to ethenyl, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

The term “aryl” is used herein to mean phenyl, naphthyl, and indene.

The terms “heteroaryl ring”, “heteroaryl moiety”, and “heteroaryl” areused herein to mean a monocyclic five- to seven-membered unsaturatedhydrocarbon ring containing at least one heteroatom selected fromoxygen, nitrogen and sulfur. Examples of heteroaryl rings include, butare not limited to, furyl, pyranyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,oxathiadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and uracil. The terms“heteroaryl ring”, “heteroaryl moiety”, and “heteroaryl” shall also usedherein to refer to fused aromatic rings comprising at least oneheteroatom selected from oxygen, nitrogen and sulfur. Each of the fusedrings may contain five or six ring atoms. Examples of fused aromaticrings include, but are not limited to, indolyl, isoindolyl, indazolyl,indolizinyl, azaindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl,benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, cinnolinyl, purinyl, and phthalazinyl.

The terms “heterocyclic rings”, “heterocyclic moieties”, and“heterocyclyl” is used herein to mean a monocyclic three- toseven-membered saturated or non-aromatic, unsaturated hydrocarbon ringcontaining at least one heteroatom selected from nitrogen, oxygen,sulphur or oxidized sulphur moieties, such as S(O)m, and m is 0 or aninteger having a value of 1 or 2. The terms “heterocyclic rings”,“heterocyclic moieties”, and “heterocyclyl” shall also refer to fusedrings, saturated or partially unsaturated, and wherein one of the ringsmay be aromatic, or heteroaromatic. Each of the fused rings may havefrom four to seven ring atoms. Examples of heterocyclyl groups include,but are not limited to, the saturated or partially saturated versions ofthe heteroaryl moieties as defined above, such as tetrahydropyrrole,tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (includingoxidized versions of the sulfur moiety), azepine, diazepine, aziridinyl,pyrrolinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 3-oxo-1-pyrrolidinyl,1,3-benzdioxol-5-yl, imidazolinyl, imidazolidinyl, indolinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino andthiomorpholino (including oxidized versions of the sulfur moiety).

The term “arylalkyl” or “heteroarylalkyl” or “heterocyclicalkyl” is usedherein to mean a C₁₋₄ alkyl (as defined above) attached to an aryl,heteroaryl or heterocyclic moiety (as also defined above) unlessotherwise indicated.

The term “sulfinyl” is used herein to mean the oxide S(O) of thecorresponding sulfide, the term “thio” refers to the sulfide, and theterm “sulfonyl” refers to the fully oxidized S(O)₂ moiety.

The term “aroyl” is used herein to mean C(O)Ar, wherein Ar is as phenyl,naphthyl, or aryl alkyl derivative such as defined above, such groupinclude but are not limited to benzyl and phenethyl.

The term “alkanoyl” is used herein to mean C(O)C₁₋₁₀ alkyl wherein thealkyl is as defined above.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described hereinabove.It is also to be understood that the present invention encompassescompounds of formula (I) in which a particular group or parameter, forexample R₅, R₆, R₉, R₁₀, R₁₁, R₁₂, R₁₃, n, m, or t, etc. may occur morethan once. In such compounds it will be appreciated that each group orparameter is independently selected from the values listed. When anyvariable occurs more than one time in a Formula (as described herein),its definition on each occurrence is independent of its definition atevery other occurrence.

With regard to stereoisomers, the compounds of the Formulas herein mayhave one or more asymmetric carbon atom and may occur as racemates,racemic mixtures and as individual enantiomers or diastereomers. Allsuch isomeric forms are included within the present invention, includingmixtures thereof

Cis (E) and trans (Z) isomerism may also occur. The present inventionincludes the individual stereoisomers of the compound of the inventionand where appropriate, the individual tautomeric forms thereof, togetherwith mixtures thereof.

Separation of diastereoisomers or cis and trans isomers may be achievedby conventional techniques, e.g. by fractional crystallisation,chromatography or H.P.L.C. A stereoisomeric mixture of the agent mayalso be prepared from a corresponding optically pure intermediate or byresolution, such as H.P.L.C. of the corresponding racemate using asuitable chiral support or by fractional crystallisation of thediastereoisomeric salts formed by reaction of the corresponding racematewith a suitable optically active acid or base, as appropriate.

Furthermore, some of the crystalline forms of the compounds of theFormulas herein may exist as polymorphs, which are included in thepresent invention.

Exemplified compounds of the compounds of this invention include theracemates, or optically active forms of the compounds of the workingexamples herein, and pharmaceutically acceptable salts thereof.

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the workingExamples.

Methods of Manufacture

The compounds of Formula (I) and (Ia), (II) and (IIa), (III) and (IIIa),(IV) and (IVa), (V) and (Va), (VI), (VIa-VIi), (VIII) and (VIIIa), (A),(A1), (B) and (B1) may be obtained by applying the synthetic proceduresdescribed herein. The synthesis provided for is applicable to producingcompounds of the Formulas herein having a variety of different R₁, R₂,X, and R₃ groups which are reacted, employing optional substituentswhich are suitably protected, to achieve compatibility with thereactions outlined herein. Subsequent deprotection, in those cases, thenaffords compounds of the nature generally disclosed. While a particularformula with particular substituent groups is shown herein, thesynthesis is applicable to all formulas and all substituent groupsherein.

Once the nucleus has been established, further compounds of Formula (I)and (Ia), (II) and (IIa), (III) and (IIIa), (IV) and (IVa), (V) and(Va), (VI) and (VIa-VIi) may be prepared by applying standard techniquesfor functional group inter-conversion, well known in the art. Forinstance: C(O)NR₄R₁₄ from CO₂CH₃ by heating with HNR₄R₁₄ in CH₃OH withor without catalytic or stoichiometric metal cyanide or Aluminumtrimethyl, e.g. NaCN; OC(O)R₆ from OH with e.g., ClC(O)R₆ in bases suchas triethylamine and pyridine; NR₁₀—C(S)NR₄R₁₄ from NHR₁₀ with analkylisothiocyanate, or thiocyanic acid and ClC(S)NR₄R₁₄; NR₁₀C(O)OR₆from NHR₁₀ with an alkyl or aryl chloroformate; NR₁₀C(O)NR₄H from NHR₁₀by treatment with an isocyanate, e.g. R₄N═C═O; NR₁₀—C(O)R₆ from NHR₁₀ bytreatment with Cl—C(O)R₆ in pyridine; C(═NR₁₀)NR₄R₁₄ from C(NR₄R₁₄)Swith H₃NR₁₀ ⁺OAc⁻ by heating in alcohol; C(NR₄R₁₄)SR₆ from C(S)NR₄R₁₄with R₆—I in an inert solvent, e.g. acetone; NR₁₀SO₂R₇ from NHR₁₀ bytreatment with ClSO₂R₇ by heating in bases such as pyridine; NR₁₀C(S)R₆from NR₁₀C(O)R₆ by treatment with Lawesson's reagent[2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide];NR₁₀SO₂CF₃ from NHR₁₀ with triflic anhydride and base wherein R₆, R₁₀,R₄ and R₁₄ are as defined in Formula (I) herein.

Precursors of the groups R₁, R₂ and R₃, can be other R₁, R₂ and R₃, etc.groups that may be interconverted by applying standard techniques forfunctional group interconversion. For example, wherein a moiety is ahalo substituted C₁₋₁₀ alkyl can be converted to the corresponding C₁₋₁₀alkylN₃ derivative by reacting with a suitable azide salt, andthereafter if desired can be reduced to the corresponding C₁₋₁₀alkylNH₂compound, which in turn can be reacted with R₇S(0)₂X′ wherein X′ is halo(e.g., chloro) to yield the corresponding C₁₋₁₀alkylNHS(0)₂R₇ compound.

Alternatively wherein the moiety is a halo-substituted C₁₋₁₀-alkyl itcan be reacted with an amine R₄R₁₄NH to yield the correspondingC₁₋₁₀-alkylNR₄R₁₄ compound, or can be reacted with an alkali metal saltof R₇SH to yield the corresponding C₁₋₁₀alkylSR₇ compound.

As noted above, it may be desirable during the synthesis of thecompounds of this invention, to derivatize reactive functional groups inthe molecule undergoing reaction so as to avoid unwanted side reactions.Functional groups such as hydroxy, amino, and acid groups are typicallyprotected with suitable groups that can be readily removed when desired.Suitable common protecting groups for use with hydroxyl groups andnitrogen groups are well known in the art and described in manyreferences, for instance, Protecting Groups in Organic Synthesis, Greeneet al., John Wiley & Sons, New York, N.Y., (2nd edition, 1991 or theearlier 1981 version). Suitable examples of hydroxyl protecting groupsinclude ether forming groups such as benzyl, and aryl groups such astert-butoxycarbonyl (Boc), silyl ethers, such as t-butyldimethyl ort-butyldiphenyl, and alkyl ethers, such as methyl connected by an alkylchain of variable link, (CR₁₀R₂₀)_(n). Amino protecting groups mayinclude benzyl, aryl such as acetyl and trialkylsilyl groups. Carboxylicacid groups are typically protected by conversion to an ester that caneasily be hydrolyzed, for example, trichloethyl, tent-butyl, benzyl andthe like.

Pharmaceutically acid addition salts of compounds of the variousFormulas described herein may be obtained in known manner, for exampleby treatment thereof with an appropriate amount of acid in the presenceof a suitable solvent.

An illustration of the preparation of compounds of the present inventionis shown in the scheme below. For purposes herein, the compounds in theSchemes are shown with an S-methyl, or S(O)₂-methyl group which isdeemed representative of the S(O)m-Rg group, wherein Rg is a C₁₋₁₀ alkylas described in the Formulas below.

Preparation of compounds with Formula (I) can be achieved throughcompound 6, which in turn may be constructed from either aldehyde 1 ornitrile 2 as shown in Scheme 1. Leaving groups (LG, described as Leavinggroup 1 (LG1) & LG2) in 1 (or 2), or elsewhere, can be independentlyselected from —Cl, —Br, —I, or —OTf and these groups can be installedthrough the transformation of another functional group (e.g. —OH) byfollowing the methods well known in the art (e.g., treatment of the —OHcompound with POCl₃).

Method A is for conversion of 1 to 2. Examples of the methods include,but are not limited to condensation with NH₂OH followed by treatmentwith thionyl chloride (SOCl₂) [e.g., Santilli et al., J. Heterocycl.Chem. (1971), 445-53] or oxidation of —CHO group to —COOH followed byformation of a primary amide (—CONH₂) and treatment with POCl₃. SuitableMethod A can also be utilized to furnish the conversion of 4 to 3—SchemeI.

Method B is for selective displacement of suitable aldehyde 1 or nitrile2 with an amine (R₃—NH₂). This type of displacement may be achievedusing triethylamine and the desired amine R₃NH₂ in chloroform at roomtemperature for 10 minutes. The reaction was very effective for a rangeof alkyl amines (78-95% yield). For aryl or heteroaryl amines, elevatedtemperatures (reflux), longer reaction time (24 hours) and presence ofNaH (or Na) may be necessary for reaction completion. Use of the basecould be omitted when 3 or more equivalent of the desired amine wereused. Other suitable bases include but are not limited to pyridine,diisopropyl ethylamine or pyrrolidine, which may also be used in anappropriate organic solvent, including but not limited to THF, diethylether, DCM, DMF, DMSO, toluene or dioxane.

Method C is for the reduction of nitrile 3 to amine 5. 5 may beconsidered a primary amine (NH₂), a secondary amine (because of —NH(R₃))or an amine (as it contains basic nitrogen). This method includes, butis not limited to BH₃ in appropriate organic solvent, such as THF, DCM,toluene, DMSO, diethyl ether or dioxane. Other suitable reductionreagents, include but are not limited to NaBH₄, LAH or DIBAL. Method Cmay require elevated temperatures (e.g., heating, refluxing orirradiating with microwave). Another example of the method ishydrogenation (H₂) in the presence of transition metals (e.g., Pd/C,Raney-Ni, PdCl₂).

Method D is for the cyclization of 5 to 6. This method requires thepresence of a cyclization reagent (e.g., CDI, COCl₂, tri-phosgene, orphenyl chloroformate methyl chloroformate). Presence of a suitable basemay help the reaction to go to completion and examples of the baseinclude, but not limited to triethyl amine, diisopropylethylamine orpyrrolidine. Reaction solvent can be DCM, THF, toluene, DMSO, or DMF.

Method E is for the installation of group —X [e.g., 6 to 7, 10 to (I),11 to (I) or 9 to 12]. This may or may not require first conversion ofsulfide (—SMe) to sulfoxide (—SOMe) or sulfone (—SO₂Me). This conversioncan be achieved using meta-chloroperoxybenzoic acid (mCPBA) in highyield and purity. Suitable oxidation methods for use herein include useof one or two equivalents of meta-chloroperoxybenzoic acid (mCPBA) orOxone® to afford either the sulfoxides or sulfones. Oxidation of thesulfides to sulfoxides or sulfones can also be effected by OsO₄ andcatalytic tertiary amine N-oxide, hydrogen peroxide, hydrogenperoxide/NaWO4, and other peracids, oxygen, ozone, organic peroxides,potassium and zinc permanganate, potassium persulfate, and sodiumhypochlorite. The subsequent displacement of sulfone group —SO₂Me(likewise, all displacement reactions mentioned below may be achievedusing the sulfide —SMe or sulfoxide —SOMe) requires a suitablenucleophile (e.g., amine, alcohol) containing the unit —X. Displacementswith amines were usually done with an excess of amine inN-methylpyrrolidine (Barvian et al., J. Med. Chem. (2000), 4606-4616). Awide range of primary amines underwent this reaction with excellentyields. In some cases (in O-displacement or sulfonamide formation) ananion of the nucleophile was prepared with base (usually sodium hydride)in DMF (or DMSO) and then added to the sulfone. Yields for thesereactions were usually lower. The sulfone may be displaced by primaryand secondary alkylamines without additional base catalysis, preferablyin a polar aprotic solvent, such as but not limited to, N-methylpyrrolidin-2-one (NMP), and at varying temperatures depending upon thenucleophilicity of the amine. For instance displacement of the sulfonewith ethanolamine, in NMP, occurred in 30 min. at 65° C., while a morehindered amine such as tris(hydroxymethyl)-aminomethane may requireelevated temperatures and extended reaction times (80° C. over a 24 hourreaction time). The sulfone can also be displaced by a primary orsecondary amine with an additional non-nucleophilic base (e.g. DIPEA) inaprotic solvents like DCM, CH₃CN, NMP, and at varying temperaturesdepending upon the nucleophilicity of the amine.

The sulfone may also be displaced with a substituted arylamine, orheteroarylamine at elevated temperatures, sometimes requiring formationof the aryl or heteroarylamine anion with sodium hydride, or othersuitable base, in DMSO. In addition, the sulfone may be readilydisplaced with aluminum salts of aryl or heteroaryl amines as previouslydescribed in the patent literature (see for example WO 99/32121, whosedisclosure is incorporated by reference herein). Likewise, sulfone maybe displaced with aryl or heteroaryl or alkyl thiols or alkyl or aryl orheteroaryl alcohols. Analogs containing sulfones as the X substituentsmay be displaced with sodium alkoxide in the alcohol, or alternativelyreactive alkoxide or phenoxide nucleophiles that may be generated fromthe alcohol or phenol with a suitable base such as sodium, NaH or sodiumbistrimethylsilyl amide in a polar aprotic solvent such as DMSO, or runas a neat reaction. Similarly the sulfone may be displaced with carbonnucleophiles. Suitable carbon nucleophiles include, but not limited toaryl Grignard reagents, alkyl Grignard reagents or relatedorganometallics such as organo lithium, zinc, tin, copper or boron.These reactions may, in some cases, require transition metal catalysissuch as with Pd or Ni catalysts.

Method F is for coupling with appropriate aryl groups to convert 7 tocompounds of Formula (I) (or 6 to 10). This transformation may beachieved using, but not limited to boronic acids (e.g., F1A) underSuzuki cross-coupling conditions, employing a palladium catalyst, suchas tetrakis(triphenylphosphine)palladium(0). The coupling conditionsinclude the use of appropriate solvents. These solvents include, but arenot limited to dioxane, THF, DMF, DMSO, NMP, acetone, water, or acombination or a mixture thereof. Preferably, the solvent is THF/H₂0, ordioxane/H₂0. The coupling conditions also include the presence ofcatalytic amount of catalysts and these catalysts include, but notlimited to tetrakis(triphenyl-phosphine)-palladium (O), PdCl2, Pd(OAc)2,(CH3CN)2PdCl2, Pd(dppf)2, or[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II).

The coupling reaction may or may not require the presence of a base.Suitable bases include, but are not limited to NaHCO₃, KHCO₃, Na₂CO₃,K₂CO₃, KOAc or combination or mixture thereof. Preferably, the base isK₂CO₃ and KOAc.

The coupling reaction may or may not require heating. The heating can becarried out with a regular oil bath or microwave irrediations and thetemperature can be varied from room temperature to >100° C., i.e. refluxtemperature of the solvent. The coupling reaction may or may not requirea sealed reaction vessal and the internal pressure can be varied fromone atmosphere to 100 atmospheres.

Alternatively, the cross-coupling may be performed using aryl orheteroaryl organozinc [e.g., aryl/heteroaryl-ZnBr, aryl/heteroaryl—ZnCl, aryl/heteroaryl-Zn-aryl/heteroaryl], organocopper [e.g.,(aryl/heteroaryl)₂-CuLi], organotin [e.g., aryl/heteroaryl-Sn(CH₃)₃,aryl/heteroaryl —Sn(CH₂CH₂CH₂CH₃)₃], (e.g., F1C), or otherorganometallic reagents (e.g., F1B) known in the art [see for exampleSolberg, J.; Undheim, K. Acta Chemica Scandinavia 1989, 62-68]. Thesetypes of coupling reactions require the use of appropriate solvents.Such solvents include, but are not limited to dioxane, THF, methylenechloride, chloroform, benzene, hexane, ethyl ether, tent-butyl methylether or a combination or a mixture thereof. The coupling reaction may,or may not, require the presence of catalytic amount of a catalyst. Suchcatalysts include, but are not limited totetrakis(triphenylphosphine)palladium (0), PdCl₂, Pd(OAc)₂,(CH₃CN)₂PdCl₂, Pd(dppf)₂. The reaction temperature can be varied from−78° C. to >100° C., i.e. reflux temperature of the solvent.Alternatively, this reaction process step may be performed undersuitable microwave irradiation conditions, if needed. This reaction may,or may not, require a sealed reaction vessel and the internal pressurecan be varied from one atmosphere to 100 atmospheres.

Method G is for coupling of 7 (or 6 or 16) with an aryl group whosestructure has a suitable precursor (e.g., acidic group —CO₂H) to thefinal substituent R₁ in Formula (I). This transformation may be achievedusing, but not limited to boronic acids (e.g., G1A) or protected acids(e.g., G1C) under Suzuki coupling conditions, (THF/H₂0, and K₂CO₃)employing a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0). If desired, these Suzukicoupling reactions may be run under microwave conditions. The boronicacid (D1A or D1E) or ester can be synthesized either by the palladiumcatalyzed coupling of an aryl halide and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi1,3,2-dioxaborolane or thetransmetalation of an aryl halide with a Grignard reagent, e.g.,isopropylmagnesium bromide followed by a trialkylborate (e.g.,triethylborate) in a suitable solvent like THF. Alternatively, thecross-coupling may be performed using aryl or heteroaryl organozinc,organocopper, organotin (e.g., G1B), or other organometallic reagents(e.g., G1D) known in the art [see for example Solberg, J.; Undheim, K.Acta Chemica Scandinavia 1989, 62-68]. Suitable de-protection isfollowed if a protected precursor (e.g., G3, G4) is used.

Method H is for the transformation of the suitable precursor (e.g.,acidic group —COOH in 8, 9, or 12) to the final substituent R₁. Thistype of transformations can be achieved by utilizing well-establishedstrategies in the art. The transformation may be done in one step (suchas coupling with amines HN(R_(10′))R_(b) under standard couplingconditions e.g. EDC/HOBT/ET₃N in CH₃CN; coupling with alcohol, HOR_(b)under standard coupling conditions, e.g. DCC, DMAP in DCM to form estersor reduction to alcohol) or in more than one step (e.g., Curtuisrearrangement to form isocyanates followed by urea formation with aminesor acid chloride formation followed by addition of an amine,HN(R_(10′))R_(b) or an alcohol, HOR_(b) plus a non-nucleophilic base,e.g. DIPEA in an aprotic solvent like DCM. This conversion may require adeprotection step to install the precursor at first (e.g., hydrolysis of—CO₂Me with LiOH/THF/water to prepare —COOH).

Preparation of compounds with Formula (Ia) can be achieved throughcompound 14, which in turn may be constructed from aldehyde 1 as shownin Scheme 2. Suitable methods from Methods A-H can be utilized tofurnish appropriate conversions in Scheme 2.

Method I is for urea formation to convert 4 to 13. This can be achievedby following strategies well-established in the art. Strategies include,but are not limited to reaction with ClSO₂NCO (or Me₃SiNCO) followed bytreatment with H₂O, reaction with COCl₂ (CDI, or triphosgene) followedby treatment with NH₃ (or NH₄OH), reaction with ClCO₂Me (or ClCO₂Et)followed by treatment with NH₃ (or NH₄OH) or reaction with NH₂CO₂(t-Bu).

Method J is for imine formation to convert 13 to 14. This can beachieved by following various strategies known in the art. Strategiesinclude, but are not limited to treatment with an acid including TFA,HOAc, HCl, H₂SO₄ or a Lewis acid (e.g., AlCl3). This conversion mayrequire elevated temperatures (e.g., heat, solvent reflux, microwaveirradiation) in appropriate organic solvents (e.g., THF, CH₂Cl₂,toluene, DMSO, CH₃CN or dioxane).

Method K is an alternative strategy to prepare compounds in Scheme 2.This method is for the de-saturation (lose of 2H in the formula) ofcompounds in Scheme 1 resulting in the corresponding compounds in Scheme2. This conversion includes, but not limited to Formula (Ia)-Scheme 2from Formula (I)-Scheme 1, 14-Scheme 2 from 6-Scheme 1. This type oftransformations can be achieved by following methods well-known in theart (e.g., treatment with NBS and AIBN in CCl₄ under elevatedtemperatures, treatment with MnO₂ in chlorobenzene under elevatedtemperatures).

Method L is for reduction of compounds in Scheme 2. This method providesan alternative strategy to synthesize compounds in Scheme 1 [e.g.,Formula (Ia)-Scheme 2 to Formula (1)-Scheme 1, 14-Scheme 2 to 6-Scheme1]. This type of conversion can be achieved by using suitable iminereduction methods published in the art (e.g., treatment with Et₃SiH,NaBH₄, H₂—Pd/C).

The compounds of Formula (II) and (IIa), (III) and (IIIa), (IV) and(IVa), (V) and (Va), (VI), (VIa-VIi), (VIII) and (VIIIa) may be obtainedby applying the synthetic procedures described above in Scheme 1 & 2except suitable reagents in Method F & G should be utilized. Examples ofthese reagents include, but not limited to those shown in Scheme 3.Suitable reagents in Method F & G for the preparation of compounds withFormula (VIb-VIi) require the presence of G5-8 in appropriate position.

Preparation of compounds with Formula (A), (A1), (B) or (B1) can beachieved from appropriate intermediates in Scheme 1 (or Scheme 2) usingproper synthetic methods known to the scientists with appropriatetraining in the literature. An example of these types of preparations isdemonstrated, but not limited to, in Scheme 4. The preparation can beachieved by reacting compound 7 (for A or B) or 16 (for A1 or B1) withanother reagent with appropriate structures as shown in Scheme 4employing Method M.

Method M is for the substitution of -LG₂ with appropriate compoundcontaining the structural unit of —Y—H. This can be achieved by heatingthe reaction mixtures in appropriate solvents. The heating method can beselected from either a regular oil bath or microwave irradiations.Solvents can be CH₂Cl₂, DMSO, DMF, toluene, benzene, CH₃CN or NMP. Thereaction may or may not require the presence of bases. An example of thebase can be selected from, but not limited to triethyl amine,diisopropyl ethyl amine, NaH, n-BuLi, tert-BuLi, tert-BuOK, Li₂CO₃,Cs₂CO₃ and pyridine. This transformation may also require the presenceof catalytic amount of catalysts containing transition metals (e.g., Pd,Cu, Ni, or W). These catalysts include, but not limited to Pd/C,Pd(PPh₃)₄ and PdCl₂. Compounds that have Y═S(O)_(m) orS(O)_(m)C(R_(y))(R_(z)) may also be prepared by the oxidation of theircorresponding compounds with Y═S or SC(R_(y))(R_(z)). Suitable oxidationmethods for use herein include, but not limited to mCPBA, Oxone, OsO₄,H₂O₂, potassium and zinc permanganate.

One aspect of the invention are the novel compounds of Formula (C) and(C1):

wherein,

-   G1, G2, G3 and G4 are as described for Formula (I) herein;-   m is 0 or an integer having a value of 1 or 2;-   Rg is a C₁₋₁₀alkyl;-   LG₂ is chlorine, bromine, iodine, or O—S(O)₂CF₃;-   R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, aryl C₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties may be optionally substituted (as defined for    Formula (I) herein.

In one embodiment, Rg is methyl. In another embodiment, m is 0 or 1.

Another aspect of the invention are compounds of Formula (D) and (D1)represented by the structure:

wherein,

-   G1, G2, G3, G4 and X are as described for Formula (I) herein;-   LG₂ is chlorine, bromine, iodine, or O—S(O)₂CF₃;-   R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, aryl C₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties may be optionally substituted (and as defined for    Formula (I)).

Another aspect of the invention are compounds of Formula (E) and (E1)represented by the structure:

wherein,

-   G1, G2, G3, G4, R₁ and (R₁)_(g) are as described for Formula (I)    herein;-   m is 0 or an integer having a value of 1 or 2;-   Rg is a C₁₋₁₀alkyl;-   LG₂ is chlorine, bromine, iodine, or O—S(O)₂CF₃;    -   R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀        alkyl, aryl, aryl C₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀        alkyl, heterocyclic or a heterocyclylC₁₋₁₀ alkyl moiety, and        wherein each of these moieties may be optionally substituted (as        defined for Formula (I) herein.        Representative examples of Formula (E) and (E1) are:-   3-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methylbenzoic    acid-   N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide-   N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide-   3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide-   3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide-   N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide-   N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide-   3-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide-   3-[8-(2,6-Difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide-   N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide-   N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide-   3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide-   3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide-   3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide-   3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide-   3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide-   3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide-   3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-N,N,4-trimethylbenzamide-   3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-N,N,4-trimethylbenzamide-   3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide-   3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide-   3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methylbenzoic    acid

It is also recognized that a similar set of formulas (F) and (F1) arecontemplated when the R₁ moiety is substituted in the 3-position of thephenyl ring, as shown in compounds of Formula (II) and (IIa). Similarintermediates are also contemplated for the remaining Formulas hereinwherein the C4 position of the pharmacophore is substituted with thevarious heteroaryl rings, e.g. G5/G6, etc. of the formulas describedherein as Formula (III) and (IIIa), (IV) and (IVa), etc.

Another aspect of the invention are compounds of Formula (G):

wherein

-   LG2 is chloro, bromo, iodo, O—S(O)₂CF₃;-   Rg is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties may be optionally substituted.

Suitably R₃ is substituted as defined herein for compounds of Formula(I).

Another aspect of the invention are compounds of Formula (H):

wherein

-   G10 is an aryl, aryl C₂₋₁₀ alkyl, heteroaryl, heteroaryl C₂₋₁₀    alkyl; aryl C₂₋₁₀ alkenyl, arylC₂₋₁₀ alkynyl, heteroaryl C₂₋₁₀    alkenyl, heteroaryl C₂₋₁₀ alkynyl, C₂₋₁₀ alkynyl, C₂₋₁₀alkenyl, or    C₂₋₁₀ alkynyl moiety, which moieties may be optionally substituted    with R₁ and (R_(1′))g;-   R₁ is C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b), C(Z)O(CR₁₀R₂₀)_(v)R_(b),    N(R_(10′))C(Z)(CR₁₀R₂₀)_(v)R_(b);    N(R_(10′))C(Z)N(R_(10′))(CR₁₀R₂₀)_(v)R_(b); or    N(R_(10′))OC(Z)(CR₁₀R₂₀)_(v)R_(b);-   R_(1′) is independently selected at each occurrence from hydrogen,    halogen, C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, cyano, nitro,    (CR₁₀R₂₀)_(v′)NR_(d)R_(d′), (CR₁₀R₂₀)_(v′)C(O)R₁₂, SR₅, S(O)R₅,    S(O)₂R₅, or (CR₁₀R₂₀)_(v′)OR₁₃;-   R_(b) is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or heterocyclylC₁₋₁₀ alkyl    moiety, which moieties excluding hydrogen, may all be optionally    substituted;-   R₅ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR_(4′)R_(14′), excluding the    moieties SR₅ being SNR_(4′)R_(14′), S(O)₂R₅ being SO₂H and S(O)R₅    being SOH;-   R_(4′) and R_(14′) are each independently selected at each    occurrence from hydrogen or C₁₋₄ alkyl, or R_(4′) and R_(14′)    together with the nitrogen to which they are attached form a    heterocyclic ring of 5 to 7 members, which ring optionally contains    an additional heteroatom selected from NR_(9′);-   R_(d) and R_(d′) are each independently selected at each occurrence    from hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkylC₁₋₄alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted; or R_(d) and R_(d′) together with the    nitrogen which they are attached form an optionally substituted    heterocyclic ring of 5 to 6 members, which ring optionally contains    an additional heteroatom selected from oxygen, sulfur or NR_(9′);-   R_(9′) is independently selected at each occurrence from hydrogen,    or C₁₋₄ alkyl;-   R₁₀ and R₂₀ are independently selected at each occurrence from    hydrogen or C₁₋₄alkyl;-   R_(10′) is independently selected at each occurrence from hydrogen    or C₁₋₄alkyl;-   R₁₂ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   R₁₃ is independently selected at each occurrence from hydrogen, C₁₋₄    alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇cycloalkylC₁₋₄ alkyl, C₅₋₇ cycloalkenyl,    C₅₋₇cycloalkenyl C₁₋₄ alkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,    heteroarylC₁₋₄ alkyl, heterocyclyl, or a heterocyclylC₁₋₄ alkyl    moiety, and wherein each of these moieties, excluding hydrogen, may    be optionally substituted;-   v is 0 or an integer having a value of 1 or 2;-   v′ is independently selected at each occurrence from 0 or an integer    having a value of 1 or 2;-   Z is independently selected at each occurrence from oxygen or    sulfur;-   Rg is an optionally substituted C₁₋₁₀ alkyl;-   R₃ is a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl C₁₋₁₀ alkyl,    aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl,    heterocyclic or a heterocyclylC₁₋₁₀ alkyl moiety, and wherein each    of these moieties may be optionally substituted.

Suitably R₃ is substituted as defined herein for compounds of Formula(I).

Compounds of Formula (H) may be made by reacting the compound disclosedas structure 4 in Scheme I found in WO 02/059083 with a suitablysubstituted isocyanate, such as ClS(O)₂NCO, or TMS —NCO in a aproticorganic solvent, such as toluene, methylene chloride, chloroform,benzene, THF, hexane, optionally with a non-nucleophilic base, such astriethylamine, diisopropyl ethylamine, pyridine, followed by reactionwith ammonia; or by reacting structure 4 with phosgene in an aproticorganic solvent, such as toluene, methylene chloride, chloroform,benzene, THF, hexane, optionally with a non-nucleophilic base, such astriethylamine, diisopropyl ethylamine, pyridine, followed by reactionwith ammonia or by reacting structure 4 with COCl₂ ormethylchloroformate or other chloroformates in an aprotic organicsolvent, such as toluene, methylene chloride, chloroform, benzene, THF,hexane, optionally with a non-nucleophilic base, such as triethylamine,diisopropyl ethylamine, pyridine, followed by reaction with ammonia.This reaction may, or may not, require heating (e.g, temperature betweenr.t. and 250° C.). The heating can be carried out in any manner and mayinclude the use of an oil bath or microwave irradiation.

Experimentals

The invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention. All temperatures aregiven in degrees centigrade, all solvents are highest available purityand all reactions run under anhydrous conditions in an Ar atmospherewhere necessary.

List of Abbreviations

DMAP: 4-(Dimethylamino)pyridine DCM: Dichloromethane DMF:N,N-Dimethylformamide dppf: 1,1′-Bis(diphenylphosphino)- ferrocene DMSO:Dimethylsulfoxide DIPEA: N,N-Diisopropylethylamine DSC: differentialscanning calorimetry EtOAc: Ethyl acetate EDC:1-(3-Dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride TFA:Trifluoroacetic anhydride M: molar L: liters mL: milliliters g: gramsmg: milligrams h: hours Aq: aqueous SPE: Solid phase extraction m-CPBA:3-Chlorobenzene- carboperoxoic acid MDAP: Mass directed auto preparationNIS: N-Iodosuccinimide HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HBTU:O-Benzotriazol-1-yl- N,N,N′,N′-tetramethyluronium hexafluorophosphateHOBT: 1-Hydoxybenzotriazole hydrate IPA: isopropyl alcohol THF:Tetrahydrofuran mol: moles mmol: millimoles satd: saturated eq:equivalents min: minutes mp: melting point rt: room temperature NMP =1-methyl-2-pyrrolidinone

LC-MS Experimental Conditions: Liquid Chromatograph

System: Shimadzu LC system with SCL-10A Controller and dual UV detectorAutosampler: Leap CTC with a Valco six port injector Column:Aquasil/Aquasil (C18 40 × 1 mm) Inj. Vol.(uL): 2.0 Solvent A: H₂O, 0.02%TFA Solvent B: MeCN, 0.018% TFA Gradient: linear Channel A: UV 214 nmChannel B: ELS Step Time (min) Dura. (min) Flow (μL/min) Sol. A Sol. B 00.00 0.00 300.00 95.00 5.00 1 0.00 0.01 300.00 95.00 5.00 2 0.01 3.20300.00 10.00 90.00 3 3.21 1.00 300.00 10.00 90.00 4 4.21 0.10 300.0095.00 5.00 5 4.31 0.40 300.00 95.00 5.00 Mass Spectrometer: PE SciexSingle Quadrupole LC/MS API-150 Polarity: Positive Acquisition mode:Profile

General Procedures

Nuclear magnetic resonance spectra were recorded at 400 MHz using on aBruker AC 400 spectrometer. CDCl₃ is deuteriochloroform, DMSO-d₆ ishexadeuteriodimethylsulfoxide, and CD₃OD (or MeOD) istetradeuteriomethanol. Chemical shifts are reported in parts per million(δ) downfield from the internal standard tetramethylsilane (TMS) or theNMR solvent. Abbreviations for NMR data are as follows: s=singlet,d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets,dt=doublet of triplets, app=apparent, br=broad. J indicates the NMRcoupling constant measured in Hertz. Mass spectra were taken on ainstruments, using electrospray (ES) ionization techniques. Alltemperatures are reported in degrees Celsius. All other abbreviationsare as described in the ACS Style Guide (American Chemical Society,Washington, D.C., 1986).

Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layerplates were used for thin layer chromatography. Both flash and gravitychromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh)silica gel. Preparative hplc were performed using a Gilson PreparativeSystem using a Luna 5u C18(2) 100A reverse phase column eluting with a10-80 gradient (0.1% TFA in acetonitrile/0.1% aqueous TFA) or a 10-80gradient (acetonitrile/water). The CombiFlash system used forpurification in this application was purchased from Isco, Inc.CombiFlash purification was carried out using a prepacked SiO₂ column, adetector with UV wavelength at 254 nm and mixed solvents.

Heating of reaction mixtures with microwave irradiations was carried outon a Smith Creator (purchased from Personal Chemistry, Forboro/Mass.,now owned by Biotage), a Emrys Optimizer (purchased from PersonalChemistry) or an Explorer (provided by CEM Discover, Matthews/N.C.)microwave.

General Procedure for Sulfoxide/Sulfone Displacement

The sulfoxide/sulfone of the template is dissolved in THF/CHCl₃ (1:1)and the amine (5 eq) and diisopropylehtylamine (3 eq) are added andallowed to stir for 1 h. The mixture is concentrated in vacuo.

General Procedure for HATU Couplings

The acid is dissolved in DMF and HATU (1 eq) is added. DIEA is added (2eq) followed by the amine (1.1 eq) and allowed to stir for 18 h. Thereaction mixture is concentrated and redissolved in CHCl₃.

Example 13-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-cyclobutyl-4-methylbenzamide1a)4-chloro-6-[2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbonitrile

To the solution of phosphorus oxychloride (65 mL, 0.70 mol) intrichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly tokeep the temperature between 5° C. to 10° C. The solution was thenwarmed up to room temperature before6-hydroxy-2-(methylthio)-4(1H)-pyrimidinone (25 g, 0.16 mol) was addedin portions. The resultant reaction mixture was heated at 80° C.overnight followed by concentration under vacuum. The resulting slurrylike residue was poured into ice, stirred for about 2 hours thenfiltered to afford the crude product. The crude product was furtherpurified by recrystalization with hexane to afford4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g, 61%).¹H-NMR (CDCl₃) δ 2.66 (s, 3H), 10.4 (s, 1H).

To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc(0.113 mL, 2.0 mmol) and EtOH (5 mL) was added4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (223 mg, 1.0 mol)to room temperature. The solution was then heated at 50° C. for about 1hour, 60° C. for about 30 minutes and 70° C. for about 30 minutes beforeit was concentrated under vacuum and washed with H₂O (10-20 mL) toafford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (190mg, 80%). LC-MS m/z 238 (M+H)⁺ 1.57 minute, 1.65 minute; ¹H-NMR (CDCl₃)δ 2.62, 2.65 (3H), 7.53, 8.30 (1H).

To 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (2.38 g,10 mmol) was added SOCl₂ (21.8 mL, 0.30 mol) slowly at room temperature.The solution was then heated at 75° C. for about 3 hours before it wasconcentrated under vacuum. The residue SOCl₂ was removed by evaporationwith toluene (5 mL) under vacuum. The resulting solid was washed withEtOH/H₂O (10 mL, 1:1) to afford4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile (2.04 g, 93%).LC-MS m/z 220 (M+H)⁺ 1.99 minute; ¹H-NMR (CDCl₃) δ 2.64 (3H).

To the solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile(2.20 g, 10.0 mmol) in DMF (10 mL) was added 2,6-difluoroaniline (2.17mL, 20.0 mmol). The solution was stirred at 50° C. for about 60 minutes.The mixture was slowly added into a solution of MeOH (20 mL) and water(30 mL). The resultant solid was filtered and washed with MeOH/H₂O (20mL, 1:1) to give4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbonitrileas a white solid (2.82 g, 90%). LC-MS m/z 313 (M+H)⁺; ¹H-NMR (CDCl₃) δ2.33 (s, 3H), 6.94 (s, 1H), 7.04 (m, 2H), 7.35 (m, 1H).

1b)5-(Aminomethyl)-6-chloro-N-(2,6-difluorophenyl)-2-(methylthio)-4-pyrimidinamine

To the solution of4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbonitrile(0.938 g) was added borane.THF complex (1.0 M, 15 mL). The reactionmixture was then heated at reflux for about 4 h until all the startingmaterial disappeared. The solution was cooled to r.t., mixed with HClsolution (6 M, 5 mL), and stirred at room temperature for about 30minutes. The solution was then mixed with NaOH solution (3 M) to pH9.0-10.0. The organic phase was separated and the aqueous layer wasextracted with EtOAc (3×30 mL). The combined organic layers were washedwith brine (50 mL), collected, dried over Na₂SO₄ and concentrated toafford the title compound 0.97 g (quantative). LC-MS m/z 317 (M+H)⁺, 1.5min (ret. time).

1c)5-Chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

To the solution of5-(aminomethyl)-6-chloro-N-(2,6-difluorophenyl)-2-(methylthio)-4-pyrimidinamine(0.317 g) in CH₂Cl₂ (5 mL) was added the mixture of carbonyl diimidazole(0.178 g) in CH₂Cl₂ (5 mL). The resultant mixture was stirred for about3 hours at r.t., mixed with CH₂Cl₂ (10 mL) and washed with HCl (1 N,2×10 mL) and H₂O (20 mL). The organic layers were collected, dried overNa₂SO₄, filtered and concentrated to provide the title compound (0.279g, 81%). LC-MS m/z 343 (M+H)⁺, 1.75 min (ret. time); ¹H-NMR (400 MHz,CDCl₃) δ 7.44-7.40 (m, 1H), 7.07-7.03 (m, 2H), 5.84 (br, 1H), 4.62 (s,2H), 2.19 (s, 3H).

1d)3-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoicacid

To a stirring solution of 3-iodo-4-methylbenzoic acid (60 g, 0.22 mol, 1eq) in degassed DMF (1400 mL, 23.3 vol.) was charged4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (81.4 g, 0.32mol, 1.4 eq) followed by potassium acetate (112 g, 1.14 mole, 5 eq) and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (18.7 g,0.02 mole, 0.1 eq). The resulting mixture was placed under a nitrogenatmosphere and was heated to 80° C. with the exclusion of lightovernight. The mixture was then concentrated under high vacuum and theresidue partitioned between EtOAc and 2M HCl. The mixture was thenfiltered and the layers separated. The aqueous phase was re-extractedwith EtOAc. The combined organics were then washed with brine, dried andevaporated to yield a brown solid that was applied to a silica plug theneluted with 2:1 cyclohexane:ethyl acetate. Fractions were then combinedand evaporated to yield a brown foam that was triturated withcyclohexane, collected by filtration then dried in vacuo to yield4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid. δ(CDCl₃) 8.50-8.49 (1H, d), 8.04-8.02 (1H, dd), 7.27-7.25 (1H, d), 2.61(3H, s), 1.36 (12H, s)

5-Chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(200 mg, 0.58 mmol) was mixed with4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(0.23 g), K₂CO₃ (0.485 g), dioxane (18 mL) and H₂O (6 mL). The resultantmixture was passed through by a stream of argon for 10 min, mixed withPd(PPh₃)₄ (34 mg) and heated at 150° C. for 1 h. It was filtered throughcelite, mixed with 1 mL acetic acid and washed with brine. The organiclayers were collected, dried over MgSO₄, filtered and concentrated andthe residue was purified by flash column chromatography to provide thetitle compound (160 mg). LC-MS m/z 443.2 (M+H)⁺, 1.98 min (ret. time).

1e)3-{8-(2,6-Difluorophenyl)-2-[4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylbenzoicacid

To the solution of the title compound from Example 1d (100 mg) inmethylene chloride (20 mL) was added m-CPBA (80 mg) at r.t, followed by1 mL of MeOH. The reaction mixture was stirred for overnight, dilutedwith EtOAc, and washed with 5% Na₂CO₃, H₂O and brine. The organic phaseswere collected, dried over MgSO₄, concentrated to afford the mixture ofsulfone and sulfoxide as a yellow solid that was used without furtherpurification.

To the solution of the above sufoxide and sulfone mixture in THF (20 mL)was added 1,1-dimethylethyl 4-piperidinylcarbamate (200 mg). Thereaction mixture was heated at reflux for 4 h. The solution was thenevaporated in vacuo and the residue was purified via flash columnchromatography to provide the title compound as a white solid. LC-MS m/z595.4 (M+H)⁺, 2.18 min (ret. time).

1f)1,1-Dimethylethyl{1-[4-{5-[(cyclobutylamino)carbonyl]-2-methylphenyl}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]-4-piperidinyl}carbamate

To the solution of the compound from Example 1d (200 mg) in methylenechloride (100 mL) were added EDC (80 mg), HOBt (60 mg) andcyclobutylamine (100 uL) at r.t. The reaction mixture was stirredovernight and evaporated in vacuo. Flash chromatography afforded thetitle compound as a white solid. LC-MS m/z 648 (M+H)⁺, 2.36 min (ret.time).

1g)3-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyrimidin-4-yl]-N-cyclobutyl-4-methylbenzamide

To the solution of the title compound from Example 1f (50 mg) in CH₂Cl₂(5 mL) was added TFA (1 mL) at r.t. The reaction mixture was stirred atr.t. for 3 h and concentrated. It was mixed with EtOAc (5 mL) and washedwith 1 M NaOH solution (5 mL), followed by brine. The organic part wascollected, dried over K₂CO₃ and concentrated in vacuo to afford the freebase of the title compound as a white solid. LC-MS m/z 548 (M+H)⁺, 1.61min (ret time).

Example 23-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(cyclopropylmethyl)-4-methylbenzamide2a)1,1-Dimethylethyl{1-[4-(5-{[(cyclopropylmethyl)amino[carbonyl}-2-methylphenyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]-4-piperidinyl}carbamate

To a solution of3-{8-(2,6-Difluorophenyl)-2-[4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylbenzoicacid (250 mg) in methylenechloride (100 mL) were added EDC (100 mg),HOBt (70 mg) and cyclopropylmethylamine (110 uL). The reaction wasstirred at r.t. overnight and evaporated in vacuo. Flash chromatographythen provided the title compound as a white solid. LC-MS m/z 648 (M+H)⁺,2.33 min (ret. time).

2b)3-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(cyclopropylmethyl)-4-methylbenzamide

To a solution of the title compound from Example 2a (50 mg) in CH₂Cl₂ (5mL) was added TFA (1 mL) at r.t. The reaction mixture was stirred for 3h and concentrated in vacuo. The residue was mixed with EtOAc (5 mL) andNaOH solution (1 M, 5 mL). The organic part was separated, washed withbrine, dried over K₂CO₃ and concentrated in vacuo to yield the free baseof the title compound as a white solid. LC-MS m/z 548 (M+H)⁺, 1.52 min(ret. time).

Example 33-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-[2-(4-fluorophenyl)ethyl]-4-methylbenzamide3a)1,1-Dimethylethyl(1-{8-(2,6-difluorophenyl)-4-[5-({[2-(4-fluorophenyl)ethyl]amino}carbonyl)-2-methylphenyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl}-4-piperidinyl)carbamate

The title compound was prepared from3-{8-(2,6-Difluorophenyl)-2-[4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylbenzoicacid by following the procedures in Example 1f except using4-fluorophenylethylamine for the amide formation. LC-MS m/z 716 (M+H)⁺,2.47 min (ret. time).

3b)3-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-[2-(4-fluorophenyl)ethyl]-4-methylbenzamide

The title compound was prepared from the compound from Example 3a byfollowing the procedures in Example 1g. LC-MS m/z 616 (M+H)⁺, 1.69 min(ret. time).

Example 43-[2-[(2-Aminoethyl)(methyl)amino]-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(cyclopropylmethyl)-4-methylbenzamide4a)N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide

To a solution of3-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoicacid (500 mg) in methylenechloride (100 mL) were added EDC (260 mg),HOBt (160 mg) and cyclopropylmethylamine (260 uL). The reaction mixturewas stirred at room temperature overnight and concentrated in vacuo. Theresidue was purified via column chromatography to provide the titlecompound as a white solid. LC-MS m/z 496 (M+H)⁺, 2.62 min (ret. time).

4b)N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide

To the solution of the compound from Example 4a (500 mg) inmethylenechloride (20 mL) and methanol (10 mL) was added m-CPBA (200 mg)at r.t. The reaction mixture was stirred for 0.5 h and filtered througha silica plug. The solution was dried over MgSO₄ and concentrated toafford the title compound as a yellow solid that was used withoutfurther purification. LC-MS m/z 512 (M+H)⁺, 1.77 min (ret time).

4c)3-[2-[(2-Aminoethyl)(methyl)amino]-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(cyclopropylmethyl)-4-methylbenzamide

To the solution of the compound from Example 4b (90 mg) in THF (10 mL)was added N-methyl ethylene diamine (70 uL) at r.t. The reaction mixturewas stirred at r.t. overnight. The solution was then evaporated in vacuoand the residue was purified by column chromatography to provide thetitle compound as a white solid. LC-MS m/z 522 (M+H)⁺, 1.55 min (ret.time).

Example 5N-(Cyclopropylmethyl)-3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzamide

To the solution ofN-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide(90 mg) in THF (10 mL) was added N-methyl ethylene diamine (70 uL) atr.t. The reaction mixture was stirred at r.t. overnight. The solutionwas then evaporated in vacuo and the residue was purified by columnchromatography to provide the title compound as a white solid (inaddition to compound 4c). LC-MS m/z 522 (M+H)⁺, 1.47 min (ret. time).

Example 6N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-7-oxo-2-(4-piperidinylamino)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide6a) 1,1-Dimethylethyl4-{[4-(5-{[(cyclopropylmethyl)amino]carbonyl}-2-methylphenyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}-1-piperidinecarboxylate

To the solution ofN-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide(100 mg) in THF (10 mL) was added 1,1-dimethylethyl4-amino-1-piperidinecarboxylate (195 mg) at r.t. The reaction mixturewas heated at reflux for 4 h. The solution was then evaporated in vacuoand the residue was purified by column chromatography to provide thetitle compound as a white solid. LC-MS m/z 648.4 (M+H)⁺, 2.16 min (ret.time).

6b)N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-7-oxo-2-(4-piperidinylamino)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide

To the solution of the compound from Example 6a (50 mg) in CH₂Cl₂ (5 mL)was added 1 mL of TFA at r.t. The reaction solution was stirred at r.t.for 3 h and concentrated in vacuo. The resultant residue was mixed withEtOAc (5 mL) and NaOH solution (1 M, 5 mL). The organic part wasseparated, washed with brine, dried over K₂CO₃ and concentrated in vacuoto yield the free base of the title compound as a white solid. LC-MS m/z548 (M+H)⁺, 1.46 min (ret. time).

Example 7N-(3-{8-(2,6-Difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylphenyl)-3-thiophenecarboxamide7a) N-(3-iodo-4-methylphenyl)-3-thiophenecarboxamide

3-Thiophenecarboxylic acid (2.0 g, 15.6 mmol) was dissolved in methylenechloride (100 mL) and 2 drops of DMF were added. The mixture was cooledto 0° C. and oxalyl chloride (1.5 mL, 17.1 mmol) was added slowly andallowed to warm to room temperature. Gas evolution was observed duringwarming. 3-Methyl-4-iodoaniline (5.45 g, 23.5 mmol), 4 drops of pyridineand K₂CO₃ (2.58 g, 18.7 mmol) are dissolved in CH₂Cl₂ (10 mL) and cooledto about 0° C. After about 1 h, the acid chloride mixture is slowlyadded to the cooled aniline mixture and allowed to warm to roomtemperature and stirred for about 18 h. The resulting mixture isfiltered, washed with ethyl acetate and the filtrate is concentrated toa brown oil. The crude material was purified via flash chromatography(10-30% ethyl acetate in hexanes) to afford the title compound (1.56 g,29%) as an off-white solid.

7b)N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-thiophenecarboxamide

The iodide from Example 7a (1.56 g, 4.5 mmol), bis(pinacolato)diboran(2.3 g, 9.0 mmol), potassium acetate (2.21 g, 22.5 mmol) and PdCl₂.dppf(0.15 g, 0.225 mmol) are dissolved in DMF (50 mL) and heated to about85° C. for about 24 h. The mixture was then concentrated to an oil andethyl acetate and water were added. The organic portion was washed withbrine and dried (Na₂SO₄). The concentrated organic layer was purifiedvia flash chromatography to give the title compound (0.212 g, 13%).

7c)N-{3-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl{-3-thiophenecarboxamide

The title compound was prepared from5-Chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-oneby following the procedures in Example 1d except usingN-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-thiophenecarboxamidefor the Suzuki cross-coupling reaction. LC-MS m/z 524 (M+H)⁺, 2.21 min(ret. time).

7d)N-(3-{8-(2,6-Difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylphenyl)-3-thiophenecarboxamide

To the solution of the compound from Example 7c (83 mg) inmethylenechloride (10 mL) was added m-CPBA (41 mg) and MeOH (1 mL). Thereaction solution was stirred overnight, diluted with EtOAc, and washedwith 5% Na₂CO₃, H₂O and brine. The organic part was separated, driedover MgSO₄, concentrated to afford the mixture of sulfone and sulfoxideas a yellow solid that was used without further purification.

To the solution of the above sufoxide and sulfone mixture in THF (10 mL)was added 2,2,6,6-tetramethyl-4-piperidinamine (123 uL). The reactionmixture was heated at reflux for 4 h and concentrated in vacuo. Flashchromatography then provided the title compound as a white solid. LC-MSm/z 632.6 (M+H), 1.68 min (ret. time).

Example 83-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-4-methylbenzamide8a)3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide

To the solution of3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoicacid (1.2 g, 2.71 mmol) in CH₂Cl₂ (80 mL) were added diisopropyl ethylamine (0.96 mL, 5.5 mmol), HATU (1.044 g, 2.75 mmol) and 4-floroaniline(0.276 mL, 2.92 mmol). The reaction mixture was stirred over night. Thereaction mixture was diluted with CH₂Cl₂ (50 mL) and water (50 mL) andshaked. The layers were separated and the organic layer was washed withbrine (75 mL), dried over Na₂SO₄, filtered and concentrated. CombiFlashchromatography (load column with DCM, mobile phase EtOAc/Hexane) thenprovided the title compound as a white solid 1.33 g (92%). LC-MS m/z 536(M+H)⁺.

8b)3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide

To a solution of the title compound from Example 8a (100 mg, 0.19 mmol)in CH₂Cl₂ (10 mL) was added mCPBA (45 mg, 0.20 mmol). The mixture wasstirred at room temperature for 10 minutes, then directly loaded onto acolumn. CombiFlash chromatography (mobile phase EtOAc/Hexane) affordedthe title compound as a white solid 90 mg (87%). LC-MS m/z 552 (M+H)⁺.

8c)3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-4-methylbenzamide

To a solution of3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide(300 mg, 0.54 mmol) in CH₂Cl₂ (30 mL) were added diisopropyl ethyl amine(0.2 mL, 1.14 mmol), N,N-dimethyl-ethylenediamine (0.3 mL, 2.7 mmol).The resultant solution was stirred at room temperature over night. Theresult mixture was concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (131 mg, 42%). LC-MS m/z 576 (M+H)⁺; ¹H-NMR (MeOD) δ 2.19 (s, 6H),2.35 (s, 3H), 2.42 (m, br, 2H), 3.24 (m, br, 2H), 4.16 (s, 2H), 7.12 (m,4H), 7.52 (m, 2H), 7.72 (m, 2H), 7.83 (s, 1H), 7.99 (d, 1H).

Example 93-{8-(2,6-difluorophenyl)-2-[[3-(dimethylamino)-propyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide

The title compound was prepared from compound from Example 8b byfollowing the procedures in Example 8c except usingN,N,N′-trimethyl-1,3-propanediamine for the displacement reaction. LC-MSm/z 604.2 (M+H)⁺, 1.77 min (ret. time); ¹H-NMR (MeOD) δ 1.60 (m, 2H),2.10 (m, 2H), 2.19 (s, 6H), 2.35 (s, 3H), 2.98 (m, 3H), 3.33 (m, 2H),4.18 (s, 2H), 7.17 (m, 4H), 7.53 (m, 2H), 7.77 (m, 2H), 7.83 (s, 1H),7.98 (d, 1H).

Example 10N-{3-[8-(2,6-difluorophenyl)-2-(methyloxy)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide10a) 4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

3-Iodo-4-methylaniline (11 g, 47.2 mmol), bis(pinacolato)diboron (24.25g, 95.5 mmol) and potassium acetate (14.3 g, 145.7 mmol) were stirredunder argon in DMF (250 mL) in an oil bath maintained at 80° C. Themixture was degassed by vigorously bubbling argon through the mixturefor 5 minutes.Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (1.875 g, 2.3 mmol) was added and the mixtureheated at 80° C. while stirring under argon for 17 hours. The mixturewas allowed to cool to room temperature and 50 g of silica gel wereadded. Most of the solvent was pumped off in vacuo. The residue wasflash chromatographed on 200 grams of silica gel eluted with 0-15% ethylacetate/hexane to give the title compound as a light yellow solid. LC-MSm/z 233 (M)⁺, 1.53 min (ret. time).

10b)5-(5-Amino-2-methylphenyl)-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

To5-chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(0.342 g, 1 mmol) and4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.256g, 1.1 mmol) in dioxane (40 mL), was added a solution of K₂CO₃ (0.417 g,3 mmol) in water (10 mL). Argon was vigorously bubbled through themixture for 5 minutes and then tetrakis(triphenyl-phosphine)palladium(0)(0.078 g, 0.05 mmol) was added. The mixture was heated in a 95° C. oilbath for 17 hours. The solvent was pumped off in vacuo, and the residuepartitioned between ethyl acetate and water. The phases separated andthe organic phase washed with brine, dried over anhydrous Na₂SO₄,filtered and evaporated. The crude product was flash chromatographed onsilica gel (20 grams) eluted with 0-10% MeOH/CH₂Cl₂ to give the titleproduct as a white solid. mp 122-125° C. LC-MS m/z 414 (M+H)⁺, 1.58 min(ret. time).

10c)N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide

The compounds5-(5-amino-2-methylphenyl)-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(0.205 g, 0.5 mmol), 3-thiophenecarboxylic acid (0.0647 g, 0.5 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.107 g,0.55 mmol), 4-(dimethylamino)pyridine (0.002 g, 0.016 mmol), andtriethylamine (0.14 mL, 1 mmol), were dissolved in chloroform (10 mL)and stirred under argon at room temperature for 16 h. The reaction wasnot complete. An additional 3-thiophenecarboxylic acid (0.13 g, 1.0mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(0.107 g, 0.55 mmol) were added and heated to 40° C. for 17 h. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic phase was washed with water (3×), brine (1×), dried overanhydrous Na₂SO₄, filtered and evaporated. The crude product was flashchromatographed on silica gel (10 g) eluted with 0-5% MeOH/CH₂Cl₂ togive the title compound as a solid. LC-MS m/z 524 (M+H)⁺, 2.2 min (ret.time).

10d)N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide

N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophene-carboxamide(0.052 g, 0.1 mmol) was dissolved in a mixture of CH₂Cl₂ (10 mL) and DMF(0.5 mL). Then 3-chloroperoxybenzoic acid (50-60%) (0.03 g, ˜0.1 mmol)was added and the mixture stirred for 45 min at room temperature.Solvent was pumped off in vacuo to give the title compound plus a smallamount of the corresponding sulfone. The mixture was used withoutfurther purification. LC-MS m/z 540 (M+H)⁺, 1.76 min (ret. time).

10e)N-{3-[8-(2,6-difluorophenyl)-2-(methyloxy)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl[-4-methylphenyl}-3-thiophenecarboxamide

The compoundN-{3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide,(0.027 g, 0.05 mmol) was dissolved in methanol (5 mL) and treated inportions with 60% NaH in mineral oil (0.1 g, 2.5 mmol) while stirringunder argon at room temperature. The mixture was stirred for 30 minutes.The solvents were pumped off in vacuo. The residue was flashchromatographed on silica gel (10 g) eluted with 0-3% MeOH/CH₂Cl₂ togive the title compound as a white solid. mp (dec) 225-228° C.; LC-MSm/z 508 (M+H)⁺, 2.04 min (ret. time).

Example 11N-{3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide

The compoundN-{3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide,(0.027 g, 0.05 mmol) was dissolved in DMF (4 mL) and 4-aminopiperidine(0.1 g, 1.0 mmol) was added. The mixture was stirred under argon at roomtemperature for 17 h. The solvents were pumped off in vacuo. The residuewas flash chromatographed on silica gel (10 g) eluted with CH₂Cl₂followed by 6:0.25:0.025, CH₂Cl₂:isopropanol:NH₄OH and then by6:0.5:0.025 CH₂Cl_(2,):isopropanol:NH₄OH to give the title compound as awhite amorphous solid. This was crystallized from CH₂Cl₂/hexane to givethe title compound as a white crystalline solid. mp (dec) 250-261° C.;LC-MS m/z 576 (M+H)⁺, 1.6 min (ret. time).

Example 12N-{3-[8-(2,6-difluorophenyl)-2-(dimethylamino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide

The compoundN-{3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide,(0.054 g, 0.1 mmol) was dissolved in a mixture of DMF (0.5 mL) andCH₂Cl₂ (10 mL), and 40% dimethylamine in water (1 mL) was added. Themixture was stirred under argon at room temperature for 3 h. Thesolvents were pumped off in vacuo. The residue was flash chromatographedon silica gel (10 g) eluted with 10-60% EtOAc/CH₂Cl₂ to give the titlecompound as a white amorphous solid. The solid was crystallized fromCH₂Cl₂/hexane to give the title compound as a white crystalline solid.mp 214-215° C.; LC-MS m/z 521 (M+H)⁺, 2.0 min (ret. time).

Example 13N-{3-[8-(2,6-difluorophenyl)-2-(ethyloxy)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide

The compoundN-{3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide,(0.054 g, 0.1 mmol) was dissolved in ethanol (5 mL) and treated inportions with 95% NaH (0.1 g, 4 mmol) while stirring under argon at roomtemperature. The mixture was stirred under argon at room temperature for1 h. The solvents were pumped off in vacuo. The residue was flashchromatographed on silica gel (10 g) eluted with 0-3% MeOH/CH₂Cl₂ togive the title compound as a white amorphous solid. This solid wascrystallized from CH₂Cl₂/hexane to give the title compound as a whitecrystalline solid. mp (dec) 199-202° C.; LC-MS m/z 522 (M+H)⁺, 2.15 min(ret. time).

Example 14N-{3-[8-(2,6-difluorophenyl)-2-(methylamino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide

The compoundN-{3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide,(0.054 g, 0.1 mmol) was dissolved in THF (20 mL) and a 2M solution ofmethylamine in THF (1 mL) was added. The mixture was stirred at roomtemperature for 4 days. The solvents were pumped off in vacuo. Theresidue was flash chromatographed on silica gel (10 g) eluted with 0-10%MeOH/CH₂Cl₂ to give the title compound as an off-white amorphous solid.mp (dec) 203-207° C.; LC-MS m/z 507 (M+H)⁺, 1.76 min (ret. time).

Example 153-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide15a)3-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide

The compound3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoicacid (0.597 g, 1.35 mmol), benzyl amine (0.445 mL, 4.0 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.311 g,1.62 mmol), 1-hydroxybenzotriazole hydrate (0.219 g, 1.62 mmol), weredissolved in CH₂Cl₂ (50 mL) and stirred under argon at room temperaturefor 16 h. The solvent was pumped off in vacuo. The reaction mixture waspartitioned between ethyl acetate and water. The organic phase washed 3×with water, 1× brine, dried over anhydrous Na₂SO₄, filtered andevaporated. The crude product was flash chromatographed on silica gel(25 g) eluted with a gradient of 6:1:0.1, CH₂Cl₂:isopropanol:NH₄OH togive the title compound. Crystallization from CH₂Cl₂/hexane gave thetitle compound as a white crystalline solid. m.p. (dec)154-159° C.;LC-MS m/z 532 (M+H)⁺, 2.24 min (ret. time).

15b)3-[8-(2,6-Difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide

The compound3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide(0.41 g, 0.77 mmol) was dissolved in CH₂Cl₂ (25 mL).3-Chloroperoxybenzoic acid (50-60%) (0.505 g, ˜1.62 mmol) was added andthe mixture stirred for 16 h at room temperature. The solvent was pumpedoff in vacuo and the residue partitioned between EtOAc and water. Theorganic phase washed with brine, dried over anhydrous Na₂SO₄, filteredand evaporated. The crude product was flash chromatographed on silicagel eluted with 0-5% MeOH/CH₂Cl₂ to give the title compound.Crystallization from CH₂Cl₂/hexane to give the title compound as a whitecrystalline solid. m.p. 239-241° C.; LC-MS m/z 564 (M+H)⁺, 2.01 min(ret. time).

15c)3-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide

The compound3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide,(0.056 g, 0.1 mmol) was dissolved in THF (5 mL) and 4-aminopiperidine(0.2 g, 2.0 mmol) was added. The mixture was stirred under argon at roomtemperature for 17 h. The solvents were pumped off in vacuo. The residuewas flash chromatographed on silica gel (15 g) eluted with 6:1:0.1,CH₂Cl₂:isopropanol:NH₄OH to give the title compound as a white amorphoussolid. m.p. (dec) 210-266° C.; LC-MS m/z 584 (M+H)⁺, 1.68 min (ret.time).

Example 163-{8-(2,6-Difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(phenylmethyl)benzamide

The compound3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide,(0.056 g, 0.1 mmol) was dissolved in THF (5 mL) and4-amino-2,2,6,6-tetramethylpiperidine (0.032 g, 0.2 mmol) was added. Themixture was stirred under argon at room temperature for 17 h. Thesolvents were pumped off in vacuo. The residue was flash chromatographedon silica gel (15 g) eluted with 6:0.5:0.05, to 6:1:0.1,CH₂Cl₂:isopropanol:NH₄OH to give the title compound as a white amorphoussolid. mp (dec) 160-165° C.; LC-MS m/z 640 (M+H)⁺, 1.62 min (ret. time).

Example 173-{8-(2,6-Difluorophenyl)-2-[[3-(dimethylamino)propyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(phenylmethyl)benzamide

The compound3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide,(0.050 g, 0.089 mmol) was dissolved in THF (5 mL) andN,N,N′-trimethyl-1,3-propanediamine (0.054 g, 0.44 mmol) was added. Themixture was stirred under argon at room temperature for 3 h. Thereaction was not complete, so additionalN,N,N′-trimethyl-1,3-propanediamine (0.108 g, 0.88 mmol) was added andthe mixture stirred at room temperature for an additional 17 h, followedby heating to 40° C. for 1 h. The solvents were pumped off in vacuo. Theresidue was taken up in EtOAc washed with 1M NaOH (2×), brine (1×),dried over anhydrous Na₂SO₄, filtered and evaporated. The residue wasflash chromatographed on silica gel (20 g) eluted with 6:1:0.05,CH₂Cl₂:isopropanol:NH₄OH to give the title compound as a white amorphoussolid. mp 124-127° C.; LC-MS m/z 600 (M+H)⁺, 1.84 min (ret. time).

Example 183-(8-(2,6-Difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(phenylmethyl)benzamide

The compound3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide,(0.050 g, 0.089 mmol) was dissolved in THF (5 mL) andN,N-dimethylethylenediamine (0.2 g, 2.2 mmol) was added. The mixture wasstirred under argon at room temperature for 4 h. The solvents werepumped off in vacuo. The residue was taken up in EtOAc washed with 1MNaOH (2×), brine (1×), dried over anhydrous Na₂SO₄, filtered andevaporated. The residue was flash chromatographed on silica gel (20 g)eluted with 6:1:0.05, CH₂Cl₂:isopropanol:NH₄OH to give the titlecompound as a white amorphous solid. mp 148-150° C.; LC-MS m/z 572(M+H)⁺, 1.68 min (ret. time).

Example 193-(8-(2,6-Difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(phenylmethyl)benzamide19a)1,1-Dimethylethyl(2-{[8-(2,6-difluorophenyl)-4-(2-methyl-5-{[(phenylmethyl)amino]carbonyl}phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}ethyl)methylcarbamate

The compound3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide,(0.065 g, 0.115 mmol) was dissolved in THF (5 mL) and1,1-dimethylethyl(2-aminoethyl)methylcarbamate (0.082 g, 0.46 mmol) wasadded. The mixture was stirred under argon at room temperature for 16 h.The solvents were pumped off in vacuo. The residue was flashchromatographed on silica gel (20 g) eluted with 0-50% EtOAc/CH₂Cl₂.This material was dissolved in CH₂Cl₂ and the title compound wasprecipitated as a white amorphous solid. mp 160-163° C.; LC-MS m/z 658(M+H)⁺, 2.07 min (ret. time).

19b)3-(8-(2,6-Difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(phenylmethyl)benzamide

The compound1,1-dimethylethyl(2-{[8-(2,6-difluorophenyl)-4-(2-methyl-5-{[(phenylmethyl)amino]carbonyl}phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}ethyl)methylcarbamate,(0.036 g, 0.055 mmol) was dissolved in CH₂Cl₂ (4 mL) and stirred underargon at 0° C. Trifluoroacetic acid (1 mL) was added and the mixturestirred under argon at 0° C. for 2 h. The solvents were pumped off invacuo, and the residue was partitioned between EtOAc and H₂O. Themixture was made basic by the addition of 1M NaOH. The organic phase waswashed with H₂O (2×), with brine (1×), dried over anhydrous Na₂SO₄,filtered and evaporated. The residue was flash chromatographed on silicagel (10 g) eluted with 6:1:0.05, CH₂Cl₂:isopropanol:NH₄OH to give thetitle compound as a white amorphous solid. mp 157-161° C.; LC-MS m/z 558(M+H)⁺, 1.49 min (ret. time).

Example 203-[8-(2,6-Difluorophenyl)-2-({2-[(1-methylethyl)amino]ethyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide

The compound3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide,(0.060 g, 0.106 mmol) was dissolved in THF (5 mL) andN-isopropylethylenediamine (0.1 g, 0.98 mmol) was added. The mixture wasstirred under argon at room temperature for 3 h. The solvents werepumped off in vacuo. The residue was taken up in EtOAc washed with 1MNaOH (1×), brine (1×), dried over anhydrous Na₂SO₄, filtered andevaporated The residue was flash chromatographed on silica gel (10 g)eluted with 6:0.5:0.05, CH₂Cl₂:ethanol:NH₄OH to give the title compoundas a off-white amorphous solid. mp 133-137° C.; LC-MS m/z 586 (M+H)⁺,1.5 min (ret. time).

Example 213-[8-(2,6-Difluorophenyl)-7-oxo-2-(4-piperidinylamino)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide21a) 1,1-Dimethylethyl4-{[8-(2,6-difluorophenyl)-4-(2-methyl-5-{[(phenylmethyl)amino]carbonyl}phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}-1-piperidinecarboxylate

The compound3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide(0.08 g, 0.14 mmol) was dissolved in CH₂Cl₂ (5 mL) and 1,1-dimethylethyl4-amino-1-piperidinecarboxylate (0.0365 g, 0.175 mmol) and triethylamine(0.0284 g, 0.28 mmol) were added. The mixture was stirred under argon atroom temperature overnight with only minor product formation. Thereaction mixture was then heated to reflux for 24 h. The reaction stillwas not complete, so additional 1,1-dimethylethyl4-amino-1-piperidinecarboxylate (0.146 g, 0 7 mmol) was added and themixture stirred at reflux for 5 days. The solvents were pumped off invacuo. The residue was taken up in EtOAc washed with 1M NaOH (2×), brine(1×), dried over anhydrous Na₂SO₄, filtered and evaporated The residuewas flash chromatographed on silica gel (20 g) eluted with 0-50%EtOAc/CH₂Cl₂ to give the title compound as a white amorphous solid. mp(dec) 167-172° C.; LC-MS m/z 684 (M+H)⁺, 2.13 min (ret. time).

21b)3-[8-(2,6-Difluorophenyl)-7-oxo-2-(4-piperidinylamino)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide

The compound 1,1-dimethylethyl4-{[8-(2,6-difluorophenyl)-4-(2-methyl-5-{[(phenylmethyl)amino]carbonyl}phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}-1-piperidinecarboxylate,(0.052 g, 0.076 mmol) was dissolved in CH₂Cl₂ (4 mL) and stirred underargon at 0° C. Trifluoroacetic acid (1 mL) was added and the mixturestirred under argon at 0° C. for 2 h. The solvents were pumped off invacuo, and the residue was partitioned between EtOAc and H₂O. Themixture was made basic by the addition of 1 M NaOH. The organic phasewas washed with H₂O (2×), brine (1×), dried over anhydrous Na₂SO₄,filtered and evaporated. The residue was flash chromatographed on silicagel (10 g) eluted with 6:2:0.2, CH₂Cl₂:ethanol:NH₄OH to give the titlecompound as a white amorphous solid. mp (dec) 172-176° C.; LC-MS m/z 584(M+H)⁺, 1.49 min (ret time).

Example 223-{8-(2,6-Difluorophenyl)-2-[(1-methyl-4-piperidinyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(phenylmethyl)benzamide

The compound3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide,(0.06 g, 0.106 mmol) was dissolved in CH₂Cl₂ (5 mL) and4-amino-1-methylpiperidine (0.031 g, 0.265 mmol) was added. The mixturewas stirred under argon at room temperature for 16 h with some productformation. The reaction was not complete, so additional4-amino-1-methylpiperidine (0.031 g, 0.265 mmol) was added and themixture stirred for an additional 24 h. The reaction still was notcomplete, and was then heated to reflux for 24 h. The solvents werepumped off in vacuo. The residue was taken up in EtOAc washed with 1MNaOH (2×), brine (1×), dried over anhydrous Na₂SO₄, filtered andevaporated The residue was flash chromatographed on silica gel (20 g)eluted with 6:2:0.2, CH₂Cl₂:ethanol:NH₄OH to give the title compound asa white amorphous solid. mp (dec) 152-154° C.; LC-MS m/z 598 (M+H)⁻,1.62 min (ret. time).

Example 23N-(3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylphenyl)-3-fluoro-4-methylbenzamide23a) 3-Fluoro-N-(3-iodo-4-methylphenyl)-4-methylbenzamide

A stirred suspension of 3-fluoro-4-methyl benzoic acid (1.15 g, 7.44mmol) in CH₂Cl₂ (50 mL) and DMF (2 drops) was cooled to 0° C. underargon and treated with oxalyl chloride (0.71 mL, 8.18 mmol) dropwise.The mixture was warmed to r.t. and stirred for 1 h. In a separate flask,3-iodo-4-methyl aniline (2.60 g, 11.16 mmol), K₂CO₃ (1.54 g, 8.93 mmol)and pyridine (4 drops) were suspended in CH₂Cl₂ (10 mL). The mixture wascooled to 0° C. under argon and the acid chloride reaction mixture wasslowly added. Upon complete addition, the reaction mixture was allowedto warm to room temperature and stirred for 3 days. The resultant solidwas filtered off and the reaction mixture was diluted with EtOAc. Theorganic phase was washed with water, brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. Diethyl ether was added and the impurities werefiltered off, affording the title compound as a brown solid. ¹H-NMR (400MHz, d₆-DMSO) δ: 10.24 (1H, s), 8.32 (1H, d), 7.77 (3H, m), 7.46 (1H,t), 7.32 (1H, t), 2.35 (3H, s), 2.32 (3H, s).

23b)Fluoro-4-methyl-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzamide

The compound 3-fluoro-N-(3-iodo-4-methylphenyl)-4-methylbenzamide (1.10g, 2.98 mmol), bis(pinacolato)diboron (1.51 g, 5.96 mmol) and potassiumacetate (0.90 g, 9.24 mmol) were suspended in DMF (50 mL) and heated to80° C. under argon. The reaction mixture was degassed with argon for 5minutes at this temperature anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.109 g, 5 mol %) was added. The reaction wasmaintained at 80° C. for 17 h. Silica gel (15 g) was added and the DMFremoved in vacuo. The dry silica gel was added to the top of a flashchromatography column and eluted with EtOAc/hexane (1:9) to yield awhite solid which was recrystallised from hexane to afford the titlecompound as a white solid. LC-MS m/z 370 (M+H)⁺, 2.59 min (ret. time).

23c)N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide

The compoundfluoro-4-methyl-N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzamide(0.323 g, 0.875 mmol) and5-chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(0.2 g, 0.583 mmol) were dissolved in 1,4-dioxane (5 mL) and potassiumcarbonate (0.322 g, 2.332 mmol) and water (1.2 mL) were added. Themixture was degassed with argon for 10 min. andtetrakis(triphenylphosphine)palladium(0) (0.034 g, 5 mol %) was added.The mixture was heated to 95° C. and maintained at this temperature for17 h. Most of the dioxane was removed in vacuo and the residue dilutedwith CH₂Cl₂. The organic phase was washed with water, brine twice, driedover Na₂SO₄, filtered and evaporated to yield the crude residue.Purification was accomplished by flash chromatography on silica gel,eluting with a CH₂Cl₂-2% MeOH/CH₂Cl₂ gradient. The resultant product wastriturated with cold diethyl ether to afford the title compound as awhite solid. mp 167-173° C.; LC-MS m/z 550 (M+H)⁺, 2.37 min (ret. time).

23d)N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide

The compoundN-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide,(0.188 g, 0.343 mmol) was suspended in CH₂Cl₂ (5 mL) and DMF (1 mL) andtreated with 3-chloroperoxybenzoic acid (50-60%) (0.192 g, 1.133 mmol)under argon. The reaction was stirred at room temperature for 4 h beforethe solvent was evaporated. The resultant solid was triturated withdiethyl ether, filtered, and washed with ether to yield the titlecompound as a white solid. mp>270° C.; LC-MS m/z 582 (M+H), 2.12 min(ret. time).

23e)N-(3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylphenyl)-3-fluoro-4-methylbenzamide

The compoundN-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide(0.070 g, 0.107 mmol) was dissolved in DMF (1.5 mL) and treated with4-amino-2,2,6,6-tetramethylpiperidine (62 ul, 0.361 mmol). Stirring atroom temperature and heating to 70° C. under argon produced no reactionso the mixture was microwaved at 200° C. for 15 min. The solvent wasremoved in vacuo and the crude product was purified by flashchromatography on silica gel, eluting with CH₂C₂-10% MeOH/CH₂C₂. Theproduct was repurified by the same method to afford the title compoundas a white solid. mp (dec) 220° C.; LC-MS m/z 659 (M+H)⁺, 1.94 min (ret.time).

Example 24N-{3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide

The compoundN-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide(0.080 g, 0.137 mmol) and 4-aminopiperidine (0.055 g, 0.551 mmol) weresuspended in THF (3 mL) and stirred under argon for 3 days. Thecompleted reaction mixture was diluted with EtOAc and the organic phasewashed with water, brine (twice), dried over Na₂SO₄, filtered andconcentrated. The crude residue was purified by flash chromatography onsilica gel, eluting with 6:0.5:0.05 CH₂Cl₂:EtOH:NH₄OH to afford thetitle compound as an off-white solid. mp 240° C.; LC-MS m/z 602 (M+H),1.79 min (ret. time).

Example 25N-{3-[8-(2,6-difluorophenyl)-2-(ethyloxy)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide

Dry ethanol (2 mL) was treated with NaH (0.0056 mg, 0.140 mmol, 60% inmineral oil) under argon and stirred for 10 min. The compoundN-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide(0.064 g, 0.110 mmol) was added in ethanol (2 mL). The reaction wasstirred under argon for 1 h and then warmed to 70° C. for 2 h. Thereaction mixture was diluted with EtOAc and the organics washed withwater, brine (twice), dried over Na₂SO₄, filtered and evaporated. Thecrude residue was purified by flash chromatography on silica gel,eluting with a CH₂Cl₂-10% EtOAc/CH₂Cl₂ gradient to afford the titlecompound as a white solid. mp 257.3-262.5° C.; LC-MS m/z 548 (M+H)⁺,2.37 min (ret. time).

Example 26N-(3-{8-(2,6-difluorophenyl)-2-[1-methylethyl)oxy]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylphenyl)-3-fluoro-4-methylbenzamide

Dry iso-propanol (2 mL) was treated with NaH (0.00612 g, 0.153 mmol, 60%in mineral oil) under argon and stirred for 10 min. The product ofExample 23d,N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide(0.070 g, 0.120 mmol) was added in iso-propanol (2 mL). The reaction wasstirred under argon for 1 hour and then warmed to 80° C. for 3 hours.The reaction mixture was diluted with EtOAc and the organics washed withwater, brine (twice), dried over Na₂SO₄, filtered and evaporated. Thecrude residue was purified by flash chromatography on silica gel,eluting with a CH₂Cl₂-10% EtOAc/CH₂Cl₂ gradient to afford the titlecompound as a white solid. mp 253.5-255.4° C.; LC-MS m/z 562 (M+H)⁺,2.44 min (ret. time).

Example 27N-{3-[8-(2,6-difluorophenyl)-7-oxo-2-(4-piperidinylamino)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide27a) 1,1-dimethylethyl4-{[8-(2,6-difluorophenyl)-4-(5-{[(3-fluoro-4-methylphenyl)carbonyl]amino}-2-methylphenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}-1-piperidinecarboxylate

The compoundN-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide,(0.1 g, 0.172 mmol), 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate(0.11 g, 0.549 mmol) and triethylamine (0.5 mL) were suspended instirred THF (4 mL) and heated to 60° C. under argon for 4 days. Dioxane(4 mL) was added and the reaction warmed to 85° C. for 2 days and then95° C. for 1 day. The reaction mixture was diluted with EtOAc and theorganics were washed with water, brine (twice), dried over Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified byflash chromatography on silica gel, eluting with 10% EtOAc/CH₂Cl₂-50%EtOAc/CH₂Cl₂ to afford the title compound as a white solid. LC-MS m/z702 (M+H)+, 2.41 min (ret. time)

27b)N-{3-[8-(2,6-difluorophenyl)-7-oxo-2-(4-piperidinylamino)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide

The product of Example 27a (0.07 g, 0.1 mmol) was suspended in CH₂Cl₂ (3mL) and treated with TFA (2 mL) on ice under argon. The reaction mixturewas stirred at 0° C. for 90 min before most of the solvent and TFA wereremoved in vacuo. The crude residue was basified with NaOH (1M) andextracted with EtOAc. The organics were washed with water, brine(twice), dried over Na₂SO₄, filtered and evaporated. The crude residuewas purified by flash chromatography on silica gel, eluting with6:0.5:0.025 CH₂Cl₂:EtOH:NH₄OH and then by prep HPLC to afford the titlecompound as a white solid. mp 218-223.5° C.; LC-MS m/z 602 (M+H)⁺, 1.84min (ret. time).

Example 28N-{3-[8-(2,6-difluorophenyl)-2-(dimethylamino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide

To the compoundN-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide(0.075 g, 0.129 mmol) in THF (4 mL) was added a 1.0 M solution ofdimethylamine in THF (0.322 mL, 0.322 mmol). The mixture was stirredunder argon for 3 days. The completed reaction mixture was diluted withEtOAc and the organic phase washed with water, brine (2×), dried overNa₂SO₄, filtered and concentrated. The crude residue was purified byflash chromatography on silica gel, eluting with 1% MeOH/CH₂Cl₂ toafford the title compound as a white solid. mp 257.8-264.3° C.; LC-MSm/z 547 (M+H)⁺, 2.24 min (ret. time).

Example 293-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide29a)3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide

To the solution of3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoicacid (1.2 g, 2.71 mmol) in CH₂Cl₂ (60 mL) was added propylamine (0.7 mL,8.51 mmol), HATU (1.08 g, 2.84 mmol) and diisopropyl ethyl amine (1.2mL, 6.9 mmol). The reaction mixture was stirred overnight. The reactionmixture was diluted with CH₂Cl₂ (50 mL) and water (50 mL) and shaken.The layers were separated and the organic layer was washed with brine(75 mL), dried over Na₂SO₄, filtered and concentrated. CombiFlashchromatography (load column with DCM, mobile phase EtOAc/Hexane) thenprovided the title compound as a white solid 1.10 g (84%). LC-MS m/z 484(M+H)⁺.

29b)3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide

To a solution of3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(600 mg, 1.24 mmol) in CH₂Cl₂ (15 mL) was added m-CPBA (293 mg, 1.31mmol). The mixture was stirred at room temperature for 10 minutes, thendirectly loaded onto a column. CombiFlash chromatography (mobile phaseEtOAc/Hexane) afforded the title compound as a white solid 475 mg (77%).LC-MS m/z 500 (M+H)⁺.

29c)3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide

To a solution of3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(430 mg, 0.86 mmol) in CH₂Cl₂ (25 mL) was addedN,N-diethyl-1,3-propanediamine (0.272 mL, 1.73 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]30MeOH [7]+NH₄OH [3]) provided the title compound as a white solid (452mg, 93%). LC-MS m/z 566 (M+H)⁻; ¹H-NMR (MeOD) 1.00 (m, 9H), 1.54 (m,2H), 1.65 (m, 2H), 2.30 (s, 3H), 2.36 (m, 2H), 2.50 (m, 4H), 3.08 (s,2H), 3.37 (m, 2H), 4.11 (s, 2H), 7.15 (m, 2H), 7.50 (m, 2H), 7.69 (s,1H), 7.85 (t, 1H).

29d)3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide

Methyl t-butyl ether (MTBE) (21.2 mL) was added to partially crystalline3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamidefree base (0.847 g). The resulting slurry was temperature-cycled withstirring from 10-40° C. overnight. The product was filtered, washed withMTBE, and dried overnight in a vacuum oven at 50° C. with a slownitrogen bleed. The yield was 88.8% (0.753 g) of crystalline3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamidefree-base with a melting onset at 179° C. (determined by DSC).

29e)3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide

Acetonitrile (140 mL) was added to partially crystalline3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamidefree base (0.867 g). The resulting mixture was temperature-cycled withstirring from 10-40° C. overnight at room temperature. The product wasfiltered, washed with acetonitrile, and dried overnight in a vacuum ovenat 50° C. with a slow nitrogen bleed. The yield was 89.2% (0.773 g) ofcrystalline3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamidefree base with a melting onset at 176° C. (determined by DSC).

29f)3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamidehydrochloride salt

Acetone (451 uL) was added to the partially crystalline3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamidefree-base (25.2 mg). Hydrochloric acid was added (1.1 equivalents; 1M in1,4-dioxane), and the resulting mixture was temperature-cycled from0-40° C. for a minimum of 48 hours. The product was filtered and driedin vacuo at room temperature. Yielded3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamideHCl salt with a melting onset at 259° C. (determined by DSC).

29g)3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamidehemi-sulfate salt

Ethanol (3.5 mL) was added to the crystalline342-{[3-(diethylamino)-propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamidefree-base (229.5 mg), and the resulting mixture was heated to 50° C.Sulfuric acid was added (1.0 equivalents; 1M in THF). The mixture wascooled to room temperature and stirred for several hours. The productwas filtered, washed with ethanol, and dried in a vacuum oven at 50° C.with a slow nitrogen bleed. The yield was 30.7% (82.7 mg) of3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamidehemi-sulfate (2 molecules of free base, 1 molecule of H₂SO₄) salt with amelting onset at 218° C. (determined by DSC).

29h)3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamidefumarate salt

Acetone with 5% water (12.2 mL) was added to the crystalline3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamidefree-base (0.608 g) and solid fumaric acid (1.0 equivalents; 124.8 mg).The resulting mixture was heated to 50° C. for one hour. The mixture wascooled to room temperature and stirred for 30 minutes. The product wasfiltered, washed with acetone with 5% water, and dried overnight in avacuum oven at 50° C. with a slow nitrogen bleed. The yield was 85.4%(0.626 g) of3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamidefumarate salt. Examination by PLM showed that the batch may containamorphous content. Acetone with 10% water (12.9 mL) was added to thefumarate salt, and the resulting mixture stirred several hours at roomtemperature. The product was filtered, washed with acetone with 10%water, and dried overnight in a vacuum oven at 50° C. with a slownitrogen bleed. The yield was 51.3% (0.376 g) of3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamidefumarate salt with a melting onset at 192° C. (determined by DSC).

29i)3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamidephosphate salt

Acetone (845 uL) was added to the crystalline3-[2-{[3-(diethylamino)propyl]-amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide_free-base(46.9 mg), and the resulting mixture was heated to 50° C. Phosphoricacid was added (1.0 equivalents; 1M in methanol). Additional methanol (5uL) was added to the resulting oily mixture to increase solubilityslightly. The mixture was cooled to room temperature and stirredovernight. The product was filtered and dried for at least one hour in avacuum oven at 50° C. with a slow nitrogen bleed. The yield was 67.1%(36.9 mg) of partially crystalline3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamidephosphate salt.

29j)3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamideethanedisulfonate salt

Acetonitrile (450 uL) was added to the crystalline3-[2-{[3-(diethylamino)propyl]-amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide_free-base(25.0 mg), and the resulting mixture was heated to 50° C.Ethanedisulfonic acid was added (1.1 equivalents; 1M in methanol). Themixture was cooled to room temperature and stirred several hours. Theproduct was filtered and dried for at least one hour in a vacuum oven at50° C. with a slow nitrogen bleed. The yield was 62.0% (20.7 mg) of3-[2-{[3-(diethylamino)-propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamideethanedisulfonate salt hydrate with a melting onset at <100° C.(determined by DSC).

Example 303-[8-(2,6-difluorophenyl)-2-({2-[(1-methylethyl)amino]ethyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide30a)3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamideExample 313-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-4-methylbenzamide31b)3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-4-methylbenzamide

To a solution of1,1-dimethylethyl(2-{[8-(2,6-difluorophenyl)-4-(5-{[(4-fluorophenyl)amino]carbonyl}-2-methylphenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}ethyl)methylcarbamate(20 mg, 0.030 mmol) in DCM (5 mL) was added TFA (0.06 mL). The reactionmixture was stirred at room temperature overnight, quenched withtriethylamine (0.2 mL) at −78° C. The residue was mixed with H₂O (5.0mL). The organic layer was separated and the aqueous layer was extractedwith DCM (3×15 mL). The combined organic phases were washed withsaturated aq. NaCl, dried over Na₂SO₄, filtered, and concentrated.Purification via a CombiFlash system (90% CH₂Cl₂/7% MeOH/3% NH₄OH) thenafforded the title compound (11 mg, 65%). LC-MS (ES) m/z 562 (M+H)⁺;¹H-NMR(MeOD) δ 2.27 (s, 3H), 2.34 (s, 3H), 2.57 (m, 2H), 3.26 (m, 2H),4.11 (s, 2H), 7.15 (m, 4H), 7.52 (m, 2H), 7.71 (m, 2H), 7.82 (s, 1H),7.97 (d, 1H).

Example 323-{8-(2,6-difluorophenyl)-2-[[2-(dimethylamino)ethyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido]4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide(40 mg, 0.073 mmol) in THF (3 mL) and DMF (0.5 mL) were addedN,N,N-trimethyl-1,2-ethanediamine (0.047 mL, 0.364 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (11 mg, 26%). LC-MS m/z 590 (M+H)⁺; ¹H-NMR (MeOD) δ 2.18 (s, 6H),2.40 (m, 5H), 3.02 (m, 3H), 3.50 (m, 2H), 4.17 (s, 2H), 7.15 (m, 4H),7.52 (m, 2H), 7.71 (m, 2H), 7.82 (s, 1H), 7.97 (d, 1H).

Example 333-{8-(2,6-difluorophenyl)-2-[4-(methylamino)-1-piperidinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide33a)1,1-dimethylethyl{1-[8-(2,6-difluorophenyl)-4-(5-{[4-fluorophenyl)amino]carbonyl}-2-methylphenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]-4-piperidinyl}methylcarbamate

To a solution of3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide(40 mg, 0.073 mmol) in THF (3 mL) and DMF (0.5 mL) were added1,1-dimethylethyl methyl(4-piperidinyl)carbamate (49 mg, 0.229 mmol) andN,N-diisopropylethylamine (0.1 mL, 0.574 mmol). The resultant solutionwas stirred at room temperature over night. The result mixture wasconcentrated. Flash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (12 mg, 25%). LC-MS m/z 702 (M+H)⁺.

33b)3-{8-(2,6-difluorophenyl)-2-[4-(methylamino)-1-piperidinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide

To a solution of1,1-dimethylethyl{1-[8-(2,6-difluorophenyl)-4-(5-{[(4-fluorophenyl)amino]carbonyl}-2-methylphenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]-4-piperidinyl}methylcarbamate(12 mg, 0.017 mmol) in DCM (3 mL) was added TFA (0.04 mL). The reactionmixture was stirred at room temperature overnight, quenched withtriethylamine (0.2 mL) at −78° C. The residue was mixed with H₂O (5.0mL). The organic layer was separated and the aqueous layer was extractedwith DCM (3×15 mL). The combined organic phases were washed withsaturated aq. NaCl, dried over Na₂SO₄, filtered, and concentrated.Purification via a CombiFlash system (90% CH₂Cl₂/7% MeOH/3% NH₄OH) thenafforded the title compound (9 mg, 87%). LC-MS (ES) m/z 602 (M+H)⁺;¹H-NMR(MeOD) δ 1.18 (m, 2H), 1.81 (d, 2H), 2.34 (s, 3H), 2.37 (s, 3H),2.58 (m, 1H), 2.78 (t, 2H), 4.11 (s, 2H), 4.40 (m, 2H), 7.15 (m, 4H),7.52 (m, 2H), 7.70 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).

Example 343-{8-(2,6-difluorophenyl)-2-[[3-(dimethylamino)propyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide34a)3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

To the solution of3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoicacid (150 mg, 0.34 mmol) in CH₂Cl₂ (10 mL) were added isopropylamine(0.087 mL, 1.02 mmol), HATU (135 mg, 0.355 mmol) and diisopropyl ethylamine (0.2 mL, 1.15 mmol). The reaction mixture was stirred over night.The reaction mixture was diluted with CH₂Cl₂ (50 mL) and water (50 mL)and shaked. The layers were separated and the organic layer was washedwith brine (75 mL), dried over Na₂SO₄, filtered and concentrated. Flashchromatography then provided the title compound as a white solid 160 g(97%). LC-MS m/z 484 (M+H)⁺.

34b)3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

To a solution of the title compound from Example 34a (160 mg, 0.33 mmol)in CH₂Cl₂ (15 mL) was added m-CPBA (78 mg, 0.35 mmol). The mixture wasstirred at room temperature for 10 minutes, then directly loaded onto acolumn. CombiFlash chromatography (mobile phase EtOAc/Hexane) affordedthe title compound as a white solid 150 mg (91%). LC-MS m/z 500 (M+H)⁺.

34c)3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

To a solution of the title compound from Example 34a (1.33 g, 2.75 mmol)in CH₂Cl₂ (130 mL) was added m-CPBA (678 mg, 3.03 mmol). The mixture wasstirred at room temperature for 10 minutes, then directly loaded onto acolumn. Flash chromatography (mobile phase EtOAc/Hexane) afforded thetitle compound as the minor product as a white solid 270 mg (19%). LC-MSm/z 516 (M+H)⁺.

34d)3-{8-(2,6-difluorophenyl)-2-[[3-(dimethylamino)propyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide

To a solution of the title compound from Example 34b (30 mg, 0.06 mmol)in THF (3 mL) were added N,N,N-trimethyl-1,3-propanediamine (0.044 mL,0.30 mmol). The resultant solution was stirred at room temperature overnight. The result mixture was concentrated. CombiFlash chromatography(mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compoundas a white solid (22 mg, 66%). LC-MS m/z 552 (M+H)⁺; ¹H-NMR (MeOD) δ1.27 (m, 6H), 1.62 (m, 2H), 2.03 (m, 2H), 2.19 (s, 6H), 2.32 (s, 3H),3.00 (s, 3H), 3.33 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.17 (t, 2H),7.44 (d, 1H), 7.54 (m, 1H), 7.69 (s, 1H), 7.86 (d, 1H).

Example 353-[8-(2,6-difluorophenyl)-2-({2-[(1-methylethyl)amino]ethyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(30 mg, 0.06 mmol) in THF (3 mL) was addedN-(1-methylethyl)-1,2-ethanediamine (0.019 mL, 0.15 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH [7]+NH₄OH[3]) provided the title compound as a whitesolid (23 mg, 71%). LC-MS m/z 538 (M+H)⁺; ¹H-NMR (MeOD) δ 1.00 (d, 3H),1.27 (d, 3H), 2.30 (s, 3H), 2.58 (m, 2H), 2.70 (m, 1H), 3.25 (m, 2H),4.07 (s, 2H), 4.23 (m, 1H), 7.16 (m, 2H), 7.44 (d, 1H), 7.50 (m, 1H),7.69 (s, 1H), 7.85 (d, 1H).

Example 363-{8-(2,6-difluorophenyl)-2-[[2-(dimethylamino)ethyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in THF (3 mL) was addedN,N,N-trimethyl-1,2-ethanediamine (0.026 mL, 0.20 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (21 mg, 97%). LC-MS m/z 538 (M+H)⁺; ¹H-NMR (MeOD) δ 1.27 (d, 6H),2.11 (s, 6H), 2.37 (s, 3H), 2.41 (m, 2H), 3.02 (m, 3H), 3.50 (m, 2H),4.11 (s, 2H), 4.23 (m, 1H), 7.16 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H),7.69 (s, 1H), 7.85 (d, 1H).

Example 373-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in THF (3 mL) was addedN,N-dimethyl-1,2-ethanediamine (0.022 mL, 0.20 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH [7]+NH₄OH[3]) provided the title compound as a whitesolid (20 mg, 95%). LC-MS m/z 524 (M +H)⁺; ¹H-NMR (MeOD) δ 1.27 (d, 6H),2.14 (s, 6H), 2.33 (s, 3H), 2.37 (m, 2H), 3.22 (m, 2H), 4.09 (s, 2H),4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H),7.85 (d, 1H).

Example 383-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamide38a)1,1-dimethylethyl(2-{[8-(2,6-difluorophenyl)-4-(2-methyl-5-{[(1-methylethyl)amino]carbonyl}phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}ethyl)methylcarbamate

To a solution of3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in THF (3 mL) was added1,1-dimethylethyl(2-aminoethyl)methylcarbamate (0.036 mL, 0.20 mmol) andN,N-diisopropylethylamine (0.1 mL, 0.574 mmol). The resultant solutionwas stirred at room temperature over night. The result mixture wasconcentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (18 mg, 74%). LC-MS m/z 610 (M+H)⁺.

38b)3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamide

To a solution of1,1-dimethylethyl(2-{[8-(2,6-difluorophenyl)-4-(2-methyl-5-{[(1-methylethyl)amino]carbonyl}phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}ethyl)methylcarbamate(18 mg, 0.030 mmol) in DCM (5 mL) was added TFA (0.05 mL). The reactionmixture was stirred at room temperature overnight, quenched withtriethylamine (0.2 mL) at −78° C. The residue was mixed with H₂O (5.0mL). The organic layer was separated and the aqueous layer was extractedwith DCM (3×15 mL). The combined organic phases were washed withsaturated aq. NaCl, dried over Na₂SO₄, filtered, and concentrated.Purification via a CombiFlash system (90% CH₂Cl₂/7% MeOH/3% NH₄OH) thenafforded the title compound (11 mg, 73%). LC-MS (ES) m/z 510 (M+H)⁺;¹H-NMR(MeOD) δ 1.27 (d, 6H), 2.26 (s, 3H), 2.30 (s, 3H), 2.56 (m, 2H),3.22 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H),7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).

Example 393-{8-(2,6-difluorophenyl)-2-[(1-methyl-4-piperidinyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide(10 mg, 0.018 mmol) in THF (5 mL) were added 1-methyl-4-piperidinamine(10 mg, 0.088 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.574 mmol).The resultant solution was stirred at room temperature over night. Theresult mixture was concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (9 mg, 83%). LC-MS m/z 602 (M+H)⁺; ¹H-NMR (MeOD) δ 1.47 (m, 2H),1.84 (m, 4H), 2.24 (s, 3H), 2.33 (s, 3H), 2.79 (m, 2H), 3.20 (m, 1H),4.13 (s, 2H), 7.15 (m, 4H), 7.53 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H),7.98 (d, 1H).

Example 403-(8-(2,6-difluorophenyl)-2-{[3-(dimethylamino)propyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in THF (3 mL) was addedN,N-dimethyl-1,3-propanediamine (0.023 mL, 0.18 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas then concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (21 mg, 97%). LC-MS m/z 538 (M+H)⁺; ¹H-NMR (MeOD) δ 1.27 (d, 6H),1.58 (m, 2H), 2.19 (s, 6H), 2.20 (m, 2H), 2.30 (s, 3H), 3.15 (m, 2H),4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H),7.69 (s, 1H), 7.85 (d, 1H).

Example 413-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(18 mg, 0.04 mmol) in THF (3 mL) was addedN,N-diethyl-1,3-propanediamine (0.028 mL, 0.18 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (17 mg, 83%). LC-MS m/z 566 (M+H)⁺; ¹H-NMR (MeOD) δ 1.00 (t, 6H),1.27 (d, 6H), 1.55 (m, 2H), 2.30 (s, 3H), 2.40 (m, 2H), 2.52 (m, 4H),3.07 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H),7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).

Example 423-(8-(2,6-difluorophenyl)-2-{[3-(dimethylamino)propyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-4-methylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide(10 mg, 0.018 mmol) in THF (3 mL) was addedN,N-dimethyl-1,3-propanediamine (0.012 mL, 0.096 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (9 mg, 84%). LC-MS m/z 590 (M+H)⁺; ¹H-NMR (MeOD) δ 1.58 (m, 2H),2.19 (s, 6H), 2.24 (m, 2H), 2.34 (s, 3H), 3.10 (m, 2H), 4.11 (s, 2H),7.15 (m, 4H), 7.53 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).

Example 433-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide(20 mg, 0.036 mmol) in THF (3 mL) was addedN,N-diethyl-1,3-propanediamine (0.030 mL, 0.19 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (14 mg, 62%). LC-MS m/z 619 (M+H)⁺; ¹H-NMR (MeOD) δ 1.00 (t, 6H),1.55 (m, 2H), 2.38 (s, 3H), 2.55 (m, 6H), 3.10 (m, 2H), 4.11 (s, 2H),7.15 (m, 4H), 7.53 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).

Example 443-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide(20 mg, 0.036 mmol) in THF (3 mL)/DMF(3 mL)/DCM(3 mL) were added(1H-imidazol-2-ylmethyl)amine dihydrochloride (50 mg, 0.52 mmol) andN,N-diisopropylethylamine (0.1 mL, 0.574 mmol). The resultant solutionwas stirred at 40° C. over night. The result mixture was concentrated.CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3])provided the title compound as a white solid (7 mg, 33%). LC-MS m/z 585(M+H)⁺; ¹H-NMR (MeOD) δ 2.33 (s, 3H), 4.13 (s, 2H), 4.42 (s, 2H), 6.92(m, 2H), 7.15 (m, 4H), 7.50 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98(d, 1H).

Example 453-[2-{[3-(dibutylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide(20 mg, 0.036 mmol) in THF (3 mL) was addedN,N-dibutyl-1,3-propanediamine (0.041 mL, 0.182 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (16 mg, 66%). LC-MS m/z 674 (M+H)⁺; ¹H-NMR (MeOD) δ 1.00 (t, 6H),1.30 (m, 4H), 1.40 (m, 4H), 1.50 (m, 2H), 2.34 (s, 3H), 2.43 (m, 6H),3.10 (m, 2H), 4.13 (s, 2H), 7.15 (m, 4H), 7.53 (m, 2H), 7.72 (m, 2H),7.82 (s, 1H), 7.98 (d, 1H).

Example 463-[8-(2,6-difluorophenyl)-2-({3-[(1-methylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide(20 mg, 0.036 mmol) in THF (3 mL) was addedN-(1-methylethyl)-1,3-propanediamine (0.025 mL, 0.179 mmol). Theresultant solution was stirred at room temperature over night. Theresult mixture was concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (14 mg, 64%). LC-MS m/z 604 (M+H)⁺; ¹H-NMR (MeOD) δ 1.00 (d, 6H),1.65 (m, 2H), 2.34 (s, 3H), 2.50 (m, 2H), 2.78 (m, 1H), 3.15 (m, 2H),4.13 (s, 2H), 7.15 (m, 4H), 7.53 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H),7.98 (d, 1H).

Example 473-[8-(2,6-difluorophenyl)-2-({3-[(1,1-dimethylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide(20 mg, 0.036 mmol) in THF (3 mL) was addedN-(1,1-dimethylethyl)-1,3-propanediamine (0.028 mL, 0.177 mmol). Theresultant solution was stirred at room temperature over night. Theresult mixture was concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (18 mg, 80%). LC-MS m/z 618 (M+H)⁺; ¹H-NMR (MeOD) δ 1.11 (s, 9H),1.58 (m, 2H), 2.34 (s, 3H), 2.48 (m, 2H), 3.15 (m, 2H), 4.13 (s, 2H),7.15 (m, 4H), 7.53 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).

Example 483-[2-{[3-(dibutylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in THF (3 mL) were addedN,N-dibutyl-1,3-propanediamine (0.041 mL, 0.182 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (24 mg, 96%). LC-MS m/z 622 (M+H)⁺; ¹H-NMR (MeOD) δ 0.98 (t, 6H),1.30 (m, 10H), 1.46 (m, 4H), 1.52 (m, 2H), 2.30 (s, 3H), 2.41 (m, 6H),3.07 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H),7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).

Example 49 3-[8-(26-difluorophenyl)-2-({3-[(1-methylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in THF (3 mL) was addedN-(1-methylethyl)-1,3-propanediamine (0.025 mL, 0.179 mmol). Theresultant solution was stirred at room temperature over night. Theresult mixture was concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (15 mg, 68%). LC-MS m/z 554 (M+H)⁺; ¹H-NMR (MeOD) δ 1.00 (d, 6H),1.27 (d, 6H), 1.60 (m, 2H), 2.31 (s, 3H), 2.50 (m, 2H), 2.75 (m, 1H),3.15 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H),7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).

Example 503-[8-(2,6-difluorophenyl)-2-({3-[(1,1-dimethylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in THF (3 mL) were addedN-(1,1-dimethylethyl)-1,3-propanediamine (0.028 mL, 0.177 mmol). Theresultant solution was stirred at room temperature over night. Theresult mixture was concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (17 mg, 75%). LC-MS m/z 566 (M+H)⁺; ¹H-NMR (MeOD) δ 1.11 (s, 9H),1.27 (d, 6H), 1.60 (m, 2H), 2.31 (s, 3H), 2.45 (m, 2H), 3.15 (m, 2H),4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H),7.69 (s, 1H), 7.85 (d, 1H).

Example 513-{8-(2,6-difluorophenyl)-2-[(1-methyl-4-piperidinyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in THF (3 mL) was added 1-methyl-4-piperidinamine (20mg, 0.176 mmol). The resultant solution was stirred at room temperatureover night. The result mixture was concentrated. CombiFlashchromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided thetitle compound as a white solid (18 mg, 82%). LC-MS m/z 550 (M+H)⁺;¹H-NMR (MeOD) δ 1.26 (d, 6H), 1.48 (m, 2H), 1.88 (m, 4H), 2.24 (s, 3H),2.29 (s, 3H), 2.75 (m, 2H), 3.18 (m, 1H), 4.09 (s, 2H), 4.23 (m, 1H),7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).

Example 523-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl{-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in THF (3 mL) were added(1H-imidazol-2-ylmethyl)amine dihydrochloride (50 mg, 0.52 mmol) andN,N-diisopropylethylamine (0.1 mL, 0.574 mmol). The resultant solutionwas stirred at room temperature over night. The result mixture wasconcentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (7 mg, 33%). LC-MS m/z 533 (M+H)⁺; ¹H-NMR (MeOD) δ 1.26 (d, 6H),2.26 (s, 3H), 4.12 (s, 2H), 4.23 (m, 1H), 4.36 (s, 2H), 6.88 (s, 2H),7.10 (t, 2H), 7.48 (m, 2H), 7.69 (s, 1H), 7.85 (d, 1H).

Example 533-{8-(2,6-difluorophenyl)-2-[[3-(dimethylamino)propyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-propylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(20 mg, 0.04 mmol) in DCM (5 mL) was addedN,N,N′-trimethyl-1,3-propanediamine (0.029 mL, 0.20 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (16 mg, 72%). LC-MS m/z 552 (M+H)⁺; ¹H-NMR (MeOD) δ 1.00 (t, 3H),1.66 (m, 4H), 2.03 (m, 2H), 2.19 (s, 6H), 2.32 (s, 3H), 2.98 (s, 3H),3.37 (m, 4H), 4.15 (s, 2H), 7.17 (t, 2H), 7.45 (d, 1H), 7.53 (m, 1H),7.69 (s, 1H), 7.85 (d, 1H).

Example 543-(8-(2,6-difluorophenyl)-2-{[3-(dimethylamino)propyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-propylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(30 mg, 0.06 mmol) in DCM (5 mL) was addedN,N-dimethyl-1,3-propanediamine (0.036 mL, 0.30 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (25 mg, 77%). LC-MS m/z 552 (M+H)⁺; ¹H-NMR (MeOD) δ 1.00 (t, 3H),1.58 (m, 2H), 1.66 (m, 2H), 2.16 (m, 2H), 2.18 (s, 6H), 2.30 (s, 3H),3.06 (m, 2H), 3.37 (m, 2H), 4.10 (s, 2H), 7.17 (t, 2H), 7.45 (d, 1H),7.53 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).

Example 553-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-propylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(30 mg, 0.06 mmol) in DCM (5 mL) was added N,N-dimethyl-1,3-propanediamine (0.033 mL, 0.30 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (31 mg, 98%). LC-MS m/z 524 (M+H)⁺; ¹H-NMR (MeOD) δ 1.00 (t, 3H),1.66 (m, 2H), 2.13 (s, 6H), 2.38 (s, 3H), 2.83 (m, 2H), 3.20 (m, 2H),3.37 (m, 2H), 4.11 (s, 2H), 7.15 (t, 2H), 7.45 (d, 1H), 7.53 (m, 1H),7.69 (s, 1H), 7.85 (d, 1H).

Example 563-[8-(2,6-difluorophenyl)-7-oxo-2-(4-phenyl-1-piperazinyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in DCM (2 mL) was added 1-phenylpiperazine (0.031 mL,0.20 mmol). The resultant solution was stirred at room temperature overnight. The result mixture was concentrated. Separation via a HPLC withTFA, then provided the title compound as a white solid (14 mg, 59%).LC-MS m/z 598 (M+H)⁺; ¹H-NMR (MeOD) δ 1.27 (d, 6H), 2.33 (s, 3H), 3.40(m, 4H), 3.87 (m, 4H), 4.11 (s, 2H), 4.23 (m, 1H), 7.17 (m, 2H), 7.29(d, 2H), 7.44 (m, 2H), 7.49 (m, 1H), 7.53 (m, 1H), 7.72 (s, 1H), 7.87(d, 1H).

Example 573-[2-(1,4′-bipiperidin-1′-yl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(150 mg, 0.30 mmol) in DCM (10 mL) was added 1,4′-bipiperidine (152 mg,0.90 mmol). The resultant solution was stirred at room temperature overnight. The result mixture was concentrated. CombiFlash chromatography(mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compoundas a white solid (35 mg, 19%). LC-MS m/z 604 (M+H)⁺; ¹H-NMR (MeOD) δ1.27 (d, 6H), 1.37 (m, 2H), 1.51 (m, 2H), 1.65 (m, 4H), 1.81 (m, 2H),2.33 (s, 3H), 2.63 (m, 5H), 2.70 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H),4.50 (m, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.68 (s, 1H),7.86 (d, 1H).

Example 583-{8-(2,6-difluorophenyl)-2-[3-(1-ethylpropyl)-1-imidazolidinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(30 mg, 0.06 mmol) in THF (1 mL)/CHCl₃ (1 mL) were added1-(1-ethylpropyl)imidazolidine (17 mg, 0.12 mmol) andN,N-diisopropylethylamine (0.6 mL, 3.0 mmol). The resultant solution wasstirred at room temperature over night. The result mixture wasconcentrated. Gilson with TFA provided the title compound as a whitesolid (18 mg, 52%). LC-MS m/z 578 (M+H)⁺; ¹H-NMR (MeOD) δ 1.27 (d, 6H),1.32 (t, 6H), 2.12 (m, 1H), 2.31 (s, 3H), 2.46 (m, 1H), 3.23 (m, 4H),3.50 (m, 4H), 4.09 (m, 1H), 4.11 (s, 2H), 4.23 (m, 1H), 4.50 (m, 2H),7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.68 (s, 1H), 7.86 (d, 1H).

Example 593-(8-(2,6-difluorophenyl)-2-{[3-(dimethylamino)-2,2-dimethylpropyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in DCM (2 mL) was addedN,N,2,2-tetramethyl-1,3-propanediamine (0.032 mL, 0.20 mmol). Theresultant solution was stirred at room temperature over night. Theresult mixture was concentrated. Gilson with TFA provided the titlecompound as a white solid (5 mg, 22%). LC-MS m/z 566 (M+H)⁺; ¹H-NMR(MeOD) δ 1.00 (s, 6H), 1.27 (d, 6H), 2.35 (s, 3H), 2.67 (s, 6H), 2.95(m, 2H), 3.21 (m, 2H), 4.20 (s, 2H), 4.23 (m, 1H), 7.18 (t, 2H), 7.52(m, 2H), 7.77 (s, 1H), 7.89 (d, 1H).

Example 603-{8-(2,6-difluorophenyl)-7-oxo-2-[4-(1-pyrrolidinyl)-1-piperidinyl]-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(80 mg, 0.16 mmol) in DCM (5 mL) was added 4-(1-pyrrolidinyl)piperidine(74 mg, 0.48 mmol). The resultant solution was stirred at roomtemperature over night. The result mixture was concentrated. CombiFlashchromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided thetitle compound as a white solid (75 mg, 79%). LC-MS m/z 590 (M+H)⁺;¹H-NMR (MeOD) δ 1.27 (d, 6H), 1.34 (m, 2H), 1.83 (m, 4H), 1.90 (m, 2H),2.31 (s, 3H), 2.40 (m, 1H), 2.68 (m, 4H), 2.77 (m, 2H), 4.11 (s, 2H),4.23 (m, 1H), 4.44 (m, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H),7.68 (s, 1H), 7.86 (d, 1H).

Example 613-[8-(2,6-difluorophenyl)-2-(4-methyl-1-piperazinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(60 mg, 0.12 mmol) in DCM (5 mL) was added 1-methylpiperazine (0.04 mL,0.36 mmol). The resultant solution was stirred at room temperature overnight. The result mixture was concentrated. CombiFlash chromatography(mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compoundas a white solid (58 mg, 90%). LC-MS m/z 536 (M+H)⁺; ¹H-NMR (MeOD) δ1.27 (d, 6H), 2.25 (s, 3H), 2.31 (s, 3H), 2.36 (m, 4H), 3.57 (m, 4H),4.11 (s, 2H), 4.23 (m, 1H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H),7.68 (s, 1H), 7.86 (d, 1H).

Example 623-[8-(2,6-difluorophenyl)-2-({2-[(1-methylethyl)amino]ethyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(30 mg, 0.06 mmol) in DCM (5 mL) was addedN-(1-methylethyl)-1,2-ethanediamine (0.037 mL, 0.30 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (15 mg, 46%). LC-MS m/z 538 (M+H)⁺; ¹H-NMR (MeOD) δ 1.00 (m, 9H),1.65 (m, 2H), 2.31 (s, 3H), 2.61 (m, 2H), 2.73 (m, 2H), 3.20 (m, 2H),3.40 (m, 1H), 4.11 (s, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H),7.69 (s, 1H), 7.86 (d, 1H).

Example 633-[8-(2,6-difluorophenyl)-2-({3-[(1-methylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(30 mg, 0.06 mmol) in DCM (5 mL) was addedN-(1-methylethyl)-1,3-propanediamine (0.042 mL, 0.30 mmol). Theresultant solution was stirred at room temperature over night. Theresult mixture was concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (13 mg, 39%). LC-MS m/z 554 (M+H)⁺; ¹H-NMR (MeOD) δ 1.00 (m, 9H),1.65 (m, 4H), 2.31 (s, 3H), 2.50 (m, 2H), 2.78 (m, 2H), 3.16 (m, 2H),3.43 (m, 1H), 4.11 (s, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H),7.69 (s, 1H), 7.86 (d, 1H).

Example 643-[2-{[3-(dibutylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(30 mg, 0.06 mmol) in DCM (5 mL) was addedN,N-dibutyl-1,3-propanediamine (0.06 mL, 0.26 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (30 mg, 83%). LC-MS m/z 622 (M+H)⁺; ¹H-NMR (MeOD) δ 1.00 (m, 10H),1.30 (m, 4H), 1.50 (m, 9H), 2.31 (s, 3H), 2.38 (m, 4H), 2.48 (m, 2H),3.08 (m, 2H), 4.11 (s, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H),7.69 (s, 1H), 7.86 (d, 1H).

Example 653-[8-(2,6-difluorophenyl)-2-({3-[(1,1-dimethylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(30 mg, 0.06 mmol) in DCM (5 mL) was addedN-(1,1-dimethylethyl)-1,3-propanediamine (0.042 mL, 0.26 mmol). Theresultant solution was stirred at room temperature over night. Theresult mixture was concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (27 mg, 80%). LC-MS m/z 622 (M+H)⁺; ¹H-NMR (MeOD) δ 1.00 (m, 12H),1.12 (m, 2H), 1.56 (m, 2H), 1.70 (m, 2H), 2.31 (s, 3H), 2.48 (m, 2H),3.12 (m, 2H), 4.11 (s, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H),7.69 (s, 1H), 7.86 (d, 1H).

Example 663-[8-(2,6-difluorophenyl)-2-(hexahydro-1H-azepin-1-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(50 mg, 0.10 mmol) in DCM (5 mL) was added hexahydro-1H-azepine (0.034mL, 0.30 mmol). The resultant solution was stirred at room temperatureover night. The result mixture was concentrated. CombiFlashchromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided thetitle compound as a white solid (39 mg, 73%). LC-MS m/z 535 (M+H)⁺;¹H-NMR (MeOD) δ 1.27 (d, 6H), 1.47 (m, 6H), 1.70 (m, 2H), 2.31 (s, 3H),3.32 (m, 2H), 3.68 (m, 2H), 4.11 (m, 2H), 4.23 (m, 1H), 7.13 (t, 2H),7.44 (d, 1H), 7.48 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).

Example 673-[8-(2,6-difluorophenyl)-7-oxo-2-(1-pyrrolidinyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(50 mg, 0.10 mmol) in DCM (5 mL) was added pyrrolidine (0.025 mL, 0.30mmol). The resultant solution was stirred at room temperature overnight. The result mixture was concentrated. CombiFlash chromatography(mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compoundas a white solid (34 mg, 67%). LC-MS m/z 507 (M+H)⁺; ¹H-NMR (MeOD) δ1.27 (d, 6H), 1.87 (m, 4H), 2.31 (s, 3H), 3.33 (m, 4H), 4.11 (m, 2H),4.23 (m, 1H), 7.13 (t, 2H), 7.44 (d, 1H), 7.48 (m, 1H), 7.70 (s, 1H),7.85 (d, 1H).

Example 683-[8-(2,6-difluorophenyl)-2-(4-morpholinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(50 mg, 0.10 mmol) in DCM (5 mL) was added morpholine (0.026 mL, 0.30mmol). The resultant solution was stirred at room temperature overnight. The result mixture was concentrated. Gilson with TFA provided thetitle compound as a white solid (40 mg, 76%). LC-MS m/z 523 (M+H)⁺;¹H-NMR (MeOD) δ 1.27 (d, 6H), 2.30 (s, 3H), 3.33 (m, 4H), 3.52 (m, 4H),4.18 (s, 2H), 4.23 (m, 1H), 7.16 (t, 2H), 7.46 (d, 1H), 7.50 (m, 1H),7.71 (s, 1H), 7.85 (d, 1H).

Example 693-{8-(2,6-difluorophenyl)-2-[3-(dimethylamino)-1-pyrrolidinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)-benzamide(30 mg, 0.06 mmol) in THF (1 mL)/CHCl₃ (1 mL) were addedN,N-dimethyl-3-pyrrolidinamine (14 mg, 0.12 mmol) andN,N-diisopropylethylamine (0.6 mL, 3.0 mmol). The resultant solution wasstirred at room temperature over night. The result mixture wasconcentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (25 mg, 76%). LC-MS m/z 550 (M+H)⁻; ¹H-NMR (MeOD) δ 1.27 (d, 6H),1.75 (m, 1H), 2.15 (m, 1H), 2.24 (s, 6H), 2.30 (s, 3H), 2.79 (m, 1H),3.15 (m, 2H), 3.45 (m, 1H), 3.71 (m, 1H), 4.11 (s, 2H), 4.23 (m, 1H),7.16 (t, 2H), 7.46 (d, 1H), 7.50 (m, 1H), 7.70 (s, 1H), 7.85 (d, 1H).

Example 703-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(36 mg, 0.072 mmol) in THF (2 mL)/CHCl₃ (2 mL) were added4-methyl-1,4′-bipiperidine (40 mg, 0.22 mmol) andN,N-diisopropylethylamine (0.1 mL, 0.5 mmol). The resultant solution wasstirred at room temperature over night. The result mixture wasconcentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (31 mg, 70%). LC-MS m/z 618 (M+H)⁻; ¹H-NMR (MeOD) δ 1.00 (d, 3H),1.22 (m, 2H), 1.27 (d, 6H), 1.38 (m, 3H), 1.68 (d, 2H), 1.81 (d, 2H),2.19 (t, 2H), 2.30 (s, 3H), 2.50 (t, 1H), 2.71 (t, 2H), 2.93 (d, 2H),4.11 (s, 2H), 4.23 (m, 1H), 4.45 (m, 2H), 7.16 (t, 2H), 7.46 (d, 1H),7.50 (m, 1H), 7.68 (s, 1H), 7.85 (d, 1H).

Example 713-{8-(2,6-difluorophenyl)-2-[4-(4-morpholinyl)-1-piperidinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(36 mg, 0.072 mmol) in THF (2 mL)/CHCl₃ (2 mL) were added4-(4-piperidinyl)morpholine (37 mg, 0.22 mmol) andN,N-diisopropylethylamine (0.1 mL, 0.5 mmol). The resultant solution wasstirred at room temperature over night. The result mixture wasconcentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (41 mg, 94%). LC-MS m/z 607 (M+H)⁻; ¹H-NMR (MeOD) δ 1.27 (d, 6H),1.33 (m, 2H), 1.83 (d, 2H), 2.30 (s, 3H), 2.38 (m, 1H), 2.55 (m, 4H),2.75 (t, 2H), 3.33 (m, 1H), 3.68 (m, 3H), 4.11 (s, 2H), 4.23 (m, 1H),4.45 (m, 2H), 7.16 (t, 2H), 7.46 (d, 1H), 7.50 (m, 1H), 7.68 (s, 1H),7.85 (d, 1H).

Example 723-{8-(2,6-difluorophenyl)-2-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(36 mg, 0.072 mmol) in THF (2 mL)/CHCl₃ (2 mL) were added1-methyl-4-(4-piperidinyl)piperazine (40 mg, 0.22 mmol) andN,N-diisopropylethylamine (0.1 mL, 0.5 mmol). The resultant solution wasstirred at room temperature over night. The result mixture wasconcentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (38 mg, 85%). LC-MS m/z 619 (M+H)⁺; ¹H-NMR (MeOD) δ 1.27 (d, 6H),1.33 (m, 2H), 1.83 (d, 2H), 2.28 (s, 3H), 2.30 (s, 3H), 2.65 (m, 11H),4.11 (m, 2H), 4.23 (m, 1H), 4.45 (m, 2H), 7.16 (t, 2H), 7.46 (d, 1H),7.50 (m, 1H), 7.68 (s, 1H), 7.85 (d, 1H).

Example 733-[2-[4-(5-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(36 mg, 0.072 mmol) in THF (2 mL)/CHCl₃ (2 mL) were added5-chloro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (51 mg,0.22 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.5 mmol). Theresultant solution was stirred at room temperature over night. Theresult mixture was concentrated. HPLC with TFA separation provided thetitle compound as a white solid (44 mg, 89%). LC-MS m/z 688 (M+H)⁻;¹H-NMR (MeOD) δ 1.27 (d, 6H), 1.75 (d, 2H), 2.00 (m, 2H), 2.86 (m, 2H),2.36 (s, 3H), 3.00 (d, 2H), 4.18 (m, 2H), 4.23 (m, 1H), 4.46 (m, 1H),4.54 (m, 2H), 7.06 (m, 2H), 7.16 (m, 3H), 7.50 (m, 2H), 7.74 (s, 1H),7.88 (d, 1H).

Example 743-(8-(2,6-difluorophenyl)-7-oxo-2-{[2-(2-pyridinyl)ethyl]amino}-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(36 mg, 0.072 mmol) in THF (2 mL)/CHCl₃ (2 mL) were added[2-(2-pyridinyl)ethyl]amine (0.026 mL, 0.22 mmol) andN,N-diisopropylethylamine (0.1 mL, 0.5 mmol). The resultant solution wasstirred at room temperature over night. The result mixture wasconcentrated. HPLC with TFA, separation then provided the title compoundas a white solid (40 mg, 98%). LC-MS m/z 568 (M+H)⁺; ¹H-NMR (MeOD) δ1.27 (d, 6H), 2.30 (s, 3H), 3.15 (m, 2H), 3.65 (m, 2H), 4.13 (m, 2H),4.23 (m, 1H), 7.18 (m, 2H), 7.51 (m, 2H), 7.68 (m, 2H), 7.90 (m, 2H),8.46 (m, 1H), 8.67 (m, 1H).

Example 753-[8-(2,6-difluorophenyl)-2-(4-methyl-1-piperazinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamidetrifluoroacetate

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide(26 mg, 0.047 mmol) in THF (2 mL)/CHCl₃ (2 mL) were added1-methylpiperazine (0.017 mL, 0.15 mmol) and N,N-diisopropylethylamine(0.03 mL, 0.015 mmol). The resultant solution was stirred at 50° C. overnight. The result mixture was concentrated. Separation via a HPLC, withTFA then provided the title compound as a white solid (13 mg, 47%).LC-MS m/z 588 (M+H)⁺; ¹H-NMR (MeOD) δ 2.34 (s, 3H), 2.91 (s, 3H), 3.11(m, 2H), 3.15 (m, 2H), 3.45 (m, 2H), 4.23 (m, 2H), 4.54 (m, 2H), 7.15(m, 4H), 7.55 (m, 2H), 7.71 (m, 2H), 7.82 (s, 1H), 8.00 (d, 1H).

Example 763-(8-(2,6-difluorophenyl)-2-{[(1-ethyl-2-pyrrolidinyl)methyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(36 mg, 0.072 mmol) in THF (2 mL)/CHCl₃ (2 mL) were added[(1-ethyl-2-pyrrolidinyl)methyl]amine (27.7 mg, 0.22 mmol) andN,N-diisopropylethylamine (0.1 mL, 0.5 mmol). The resultant solution wasstirred at room temperature over night. The result mixture wasconcentrated. Purification via a HPLC with TFA then provided the titlecompound as a white solid (30 mg, 74%). LC-MS m/z 564 (M+H)⁺; ¹H-NMR(MeOD) δ 0.85 (m, 3H), 1.27 (d, 6H), 1.93 (m, 2H), 2.06 (m, 2H), 2.35(s, 3H), 2.88 (m, 1H), 3.08 (m, 1H), 3.28 (m, 1H), 3.45 (m, 2H), 3.51(m, 2H), 4.13 (m, 2H), 4.23 (m, 1H), 7.18 (m, 2H), 7.51 (m, 2H), 7.74(s, 1H), 7.90 (d, 1H).

Example 773-[2-(1,4′-bipiperidin-1′-yl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(17 mg, 0.034 mmol) in DCM (2 mL) was added 1,4′-bipiperidine (16 mg,0.10 mmol). The resultant solution was stirred at room temperature overnight. The result mixture was concentrated. CombiFlash chromatography(mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compoundas a white solid (13 mg, 63%). LC-MS m/z 604 (M+H)⁺; ¹H-NMR (MeOD) δ1.00 (t, 3H), 1.50 (m, 4H), 1.68 (m, 6H), 1.92 (m, 2H), 2.31 (s, 3H),2.73 (m, 2H), 2.90 (m, 5H), 3.37 (m, 2H), 4.16 (m, 2H), 4.52 (m, 2H),7.16 (m, 2H), 7.46 (m, 1H), 7.51 (m, 1H), 7.68 (s, 1H), 7.86 (d, 1H).

Example 783-{8-(2,6-difluorophenyl)-7-oxo-2-[4-(1-pyrrolidinyl)-1-piperidinyl]-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-propylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(17 mg, 0.034 mmol) in DCM (2 mL) was added 4-(1-pyrrolidinyl)piperidine(15 mg, 0.10 mmol). The resultant solution was stirred at roomtemperature over night. The result mixture was concentrated. CombiFlashchromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided thetitle compound as a white solid (11 mg, 55%). LC-MS m/z 592 (M+H)⁺;¹H-NMR (MeOD) δ 1.00 (t, 3H), 1.34 (m, 2H), 1.68 (m, 3H), 1.90 (m, 5H),2.31 (s, 3H), 2.36 (m, 1H), 2.68 (m, 6H), 3.37 (m, 2H), 4.11 (m, 2H),4.42 (m, 2H), 7.16 (m, 2H), 7.46 (m, 1H), 7.51 (m, 1H), 7.68 (s, 1H),7.86 (d, 1H).

Example 793-[8-(2,6-difluorophenyl)-2-(4-methyl-1-piperazinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(17 mg, 0.034 mmol) in DCM (2 mL) was added 1-methylpiperazine (0.011mL, 0.10 mmol). The resultant solution was stirred at room temperatureover night. The result mixture was concentrated. CombiFlashchromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided thetitle compound as a white solid (11 mg, 60%). LC-MS m/z 536 (M+H)⁺;¹H-NMR (MeOD) δ 1.00 (t, 3H), 1.66 (m, 2H), 2.28 (s, 3H), 2.31 (s, 3H),2.42 (m, 4H), 3.37 (m, 2H), 3.57 (m, 4H), 4.13 (m, 2H), 7.16 (m, 2H),7.46 (m, 1H), 7.51 (m, 1H), 7.68 (s, 1H), 7.86 (d, 1H).

Example 803-(8-(2,6-difluorophenyl)-7-oxo-2-{[2-(1-pyrrolidinyl)ethyl]amino}-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in DCM (2 mL) was added[2-(1-pyrrolidinyl)ethyl]amine (0.025 mL, 0.20 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. Separation via a HPLC with TFA provided the titlecompound as a white solid (10 mg, 45%). LC-MS m/z 550 (M+H)⁺; ¹H-NMR(MeOD) δ 1.27 (d, 6H), 1.70 (m, 2H), 2.04 (m, 2H), 2.31 (s, 3H), 2.91(m, 2H), 3.26 (m, 2H), 3.53 (m, 4H), 4.16 (m, 2H), 4.23 (m, 1H), 7.18(m, 2H), 7.48 (m, 1H), 7.54 (m, 1H), 7.71 (s, 1H), 7.86 (d, 1H).

Example 813-(8-(2,6-difluorophenyl)-2-{[2-(4-morpholinyl)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in DCM (2 mL) was added [2-(4-morpholinyl)ethyl]amine(0.026 mL, 0.20 mmol). The resultant solution was stirred at roomtemperature over night. The result mixture was concentrated. Separationvia a HPLC with TFA then provided the title compound as a white solid(11 mg, 49%). LC-MS m/z 566 (M+H)⁺; ¹H-NMR (MeOD) δ 1.27 (d, 6H), 2.33(s, 3H), 3.14 (m, 2H), 3.22 (m, 3H), 3.58 (m, 5H), 3.90 (m, 2H), 4.16(m, 2H), 4.23 (m, 1H),7.18 (m, 2H), 7.50 (m, 1H), 7.54 (m, 1H), 7.74 (s,1H), 7.88 (d, 1H).

Example 823-(8-(2,6-difluorophenyl)-7-oxo-2-{[3-(2-oxo-1-pyrrolidinyl)propyl]amino}-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in DCM (2 mL) was added1-(3-aminopropyl)-2-pyrrolidinone (0.028 mL, 0.20 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. Separation via a HPLC with TFA then provided the titlecompound as a white solid (10 mg, 43%). LC-MS m/z 578 (M+H)⁺; ¹H-NMR(MeOD) δ 1.27 (d, 6H), 1.66 (m, 2H), 2.05 (m, 2H), 2.35 (m, 2H), 2.39(s, 3H), 3.16 (m, 4H), 3.40 (m, 2H), 4.16 (m, 2H), 4.23 (m, 1H),7.22 (m,2H), 7.55 (m, 1H), 7.62 (m, 1H), 7.83 (s, 1H), 7.95 (d, 1H).

Example 833-(8-(2,6-difluorophenyl)-2-{[3-(4-morpholinyl)propyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in DCM (2 mL) was added[3-(4-morpholinyl)propyl]amine (0.029 mL, 0.20 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. Separation via a HPLC with TFA then provided the titlecompound as a white solid (10 mg, 43%). LC-MS m/z 580 (M+H)⁺; ¹H-NMR(MeOD) δ 1.27 (d, 6H), 1.87 (m, 2H), 2.33 (s, 3H), 3.14 (m, 4H), 3.30(m, 2H), 3.39 (m, 2H), 3.68 (m, 2H), 4.01 (m, 2H), 4.16 (m, 2H), 4.23(m, 1H),7.18 (m, 2H), 7.48 (m, 1H), 7.55 (m, 1H), 7.72 (s, 1H), 7.89 (d,1H).

Example 843-{8-(2,6-difluorophenyl)-2-[4-(diphenylmethyl)-1-piperazinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in DCM (2 mL) was added 1-(diphenylmethyl)piperazine(50 mg, 0.20 mmol). The resultant solution was stirred at roomtemperature over night. The result mixture was concentrated. Separationvia a HPLC with TFA then provided the title compound as a white solid(13 mg, 47%). LC-MS m/z 688 (M+H)⁺; ¹H-NMR (MeOD) δ 1.27 (d, 6H), 2.28(s, 3H), 3.17 (m, 5H), 3.70 (m, 3H), 4.18 (m, 2H), 4.23 (m, 1H), 5.39(m, 1H), 7.13 (m, 2H), 7.45 (m, 8H), 7.59 (m, 4H), 7.66 (s, 1H), 7.85(d, 1H).

Example 853-[2-{[4-(diethylamino)-1-methylbutyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

To a solution of compound3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in DCM (2 mL) was addedN¹,N¹-diethyl-1,4-pentanediamine (0.039 mL, 0.20 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. Separation via a HPLC with TFA then provided the titlecompound as a white solid (7 mg, 29%). LC-MS m/z 594 (M+H)⁺; ¹H-NMR(MeOD) δ 1.10 (d, 3H), 1.27 (m, 12H), 1.51 (m, 2H), 1.65 (m, 2H), 2.34(s, 3H), 3.02 (m, 2H), 3.17 (m, 4H), 3.38 (m, 1H), 4.16 (m, 2H), 4.23(m, 1H),7.18 (m, 2H), 7.48 (m, 1H), 7.54 (m, 1H), 7.72 (s, 1H), 7.89 (d,1H).

Example 863-{8-(2,6-difluorophenyl)-7-oxo-2-[4-(1-pyrrolidinyl)-1-piperidinyl]-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide86a)5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

To a solution of3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoicacid (1.71 g, 5 mmol) in CH₂Cl₂ (60 mL) was added m-CPBA (1.17 g, 5.2mmol). The mixture was stirred at room temperature for 10 minutes, thendirectly loaded onto a column. Flash chromatography (mobile phaseEtOAc/Hexane) afforded the title compound as a white solid 1.58 g (88%).LC-MS m/z 358 (M+H)⁺.

86b)5-chloro-1-(2,6-difluorophenyl)-7-[4-(1-pyrrolidinyl)-1-piperidinyl]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

To a solution of the title compound from Example 86a (250 mg, 0.70 mmol)in DCM (10 mL) were added 4-(1-pyrrolidinyl)piperidine (323 mg, 2.1mmol) and N,N-diisopropylethylamine (0.3 mL, 1.7 mmol). The resultantsolution was stirred at room temperature over night. The result mixturewas concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (253 mg, 81%). LC-MS m/z 449 (M+H)⁺.

86c)3-{8-(2,6-difluorophenyl)-7-oxo-2-[4-(1-pyrrolidinyl)-1-piperidinyl]-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide

To a solution of the title compound from Example 86b (18 mg, 0.04 mmol)in dioxane (1.5 mL)/water (0.5 mL) were added potassium carbonate (34mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium(0) (2.3 mg, 0.002mmol) andN-(4-fluorophenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(22 mg, 0.062 mmol). The reaction mixture was bubbled with N₂ for 5mins, then microwaved at 150° C. for 30 mins. The reaction mixture wasconcentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (14 mg, 54%). LC-MS m/z 642 (M+H)⁺; ¹H-NMR (MeOD) δ 1.32 (m, 2H),1.80 (m, 4H), 1.88 (m, 2H), 2.24 (m, 1H), 2.33 (s, 3H), 2.62 (m, 4H),2.74 (t, 2H), 4.17 (m, 2H), 4.40 (m, 2H), 7.12 (m, 4H), 7.52 (m, 2H),7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).

Example 873-[2-(1,4′-bipiperidin-1′-yl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide87a)7-(1,4′-bipiperidin-1′-yl)-5-chloro-1-(2,6-difluorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

To a solution of5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(200 mg, 0.56 mmol) in DCM (10 mL) were added 1,4′-bipiperidine (270 mg,1.61 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.7 mmol). Theresultant solution was stirred at room temperature over night. Theresult mixture was concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a whitesolid (298 mg, 83%). LC-MS m/z 463 (M+H)⁺.

87b)3-[2-(1,4′-bipiperidin-1′-yl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide

To a solution of compound7-(1,4′-bipiperidin-1′-yl)-5-chloro-1-(2,6-difluorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(18 mg, 0.04 mmol) in dioxane (1.5 mL)/water (0.5 mL) were addedpotassium carbonate (34 mg, 0.25 mmol),tetrakis(triphenylphosphine)palladium(0) (2.3 mg, 0.002 mmol) andN-(4-fluorophenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(22 mg, 0.062 mmol). The reaction mixture was bubbled with N₂ for 5mins, then microwaved at 150° C. for 30 mins. The reaction mixture wasconcentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided the title compound as a white solid (13 mg, 51%).LC-MS m/z 656 (M+H)⁺; ¹H-NMR (MeOD) δ 1.37 (m, 2H), 1.48 (m, 2H), 1.60(m, 4H), 1.80 (m, 2H), 2.33 (s, 3H), 2.56 (m, 5H), 2.72 (t, 2H), 4.17(m, 2H), 4.46 (m, 2H), 7.12 (m, 4H), 7.52 (m, 2H), 7.72 (m, 2H), 7.82(s, 1H), 7.98 (d, 1H).

Example 883-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(1-methylethyl)benzamide88a)5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)ethyl]amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

To a solution of5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(800 mg, 2.23 mmol) in DCM (45 mL) were addedN,N-dimethylethylenediamine (0.36 mL, 3.23 mmol) and triethylamine (0.63mL, 4.5 mmol). The resultant solution was stirred at room temperatureover night. The result mixture was concentrated. CombiFlashchromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) provided thetitle compound as a white solid (730 mg, 85%). LC-MS m/z 383 (M+H)⁺.

88b)3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicacid

To a solution of the title compound from Example 88a (100 mg, 0.26 mmol)in dioxane (9 mL)/water (3 mL) were added potassium carbonate (217 mg,1.57 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol)and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (65 mg,0.39 mmol). The reaction mixture was bubbled with N₂ for 5 mins, thenmicrowaved at 150° C. for 30 mins. The reaction mixture wasconcentrated. To the concentrated mixture were added DMSO (2 mL), H₂O(0.5 mL) and AcOH (0.05 mL). Separation via a HPLC then provided thetitle compound as a white solid (120 mg, 98%). LC-MS m/z 469 (M+H).

88c)3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino{-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(1-methylethyl)benzamide

To the solution of the title compound from Example 88b (23 mg, 0.05mmol) in CH₂Cl₂ (3 mL) were added isopropylamine (0.005 mL, 0.055 mmol),HATU (20 mg, 0.052 mmol) and diisopropyl ethyl amine (0.05 mL, 0.3mmol). The reaction mixture was stirred over night. The reaction mixturewas diluted with CH₂Cl₂ (5 mL) and water (5 mL) and shaked. The layerswere separated and the organic layer was washed with brine (8 mL), driedover Na₂SO₄, filtered and concentrated. CombiFlash chromatography(mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) then provided the titlecompound as a white solid (20 mg, 80%). LC-MS m/z 510 (M+H)⁺; ¹H-NMR(MeOD) δ 1.27 (d, 6H), 2.16 (s, 6H), 2.36 (m, 2H), 3.28 (m, 2H), 4.23(m, 1H), 4.46 (m, 2H), 7.14 (m, 2H), 7.49 (m, 1H), 7.61 (m, 1H), 7.72(m, 1H), 7.96 (d, 1H), 8.00 (s, 1H).

Example 893-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzamide

To the solution of3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicacid (23 mg, 0.05 mmol) in CH₂Cl₂ (3 mL) were added ammonia (2.0 M soln.in isopropanol, 0.0275 mL, 0.055 mmol), HATU (20 mg, 0.052 mmol) anddiisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture wasstirred over night. The reaction mixture was diluted with CH₂Cl₂ (5 mL)and water (5 mL) and shaked. The layers were separated and the organiclayer was washed with brine (8 mL), dried over Na₂SO₄, filtered andconcentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) then provided the title compound as awhite solid (6 mg, 26%). LC-MS m/z 468 (M+H)⁺; ¹H-NMR (MeOD) δ 2.16 (s,6H), 2.36 (m, 2H), 3.20 (m, 2H), 4.46 (s, 2H), 7.14 (m, 2H), 7.49 (m,1H), 7.61 (m, 1H), 7.75 (m, 1H), 8.00 (d, 1H), 8.07 (s, 1H).

Example 903-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,N-dimethylbenzamide

To the solution of3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicacid (23 mg, 0.05 mmol) in CH₂Cl₂ (3 mL) were added dimethylamine (2.0 Msoln. in THF, 0.0275 mL, 0.055 mmol), HATU (20 mg, 0.052 mmol) anddiisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture wasstirred over night. The reaction mixture was diluted with CH₂Cl₂ (5 mL)and water (5 mL) and shaked. The layers were separated and the organiclayer was washed with brine (8 mL), dried over Na₂SO₄, filtered andconcentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) then provided the title compound as awhite solid (10 mg, 41%). LC-MS m/z 496 (M+H)⁺; ¹H-NMR (MeOD) δ 2.15 (s,6H), 2.36 (m, 2H), 3.15 (s, 3H), 3.06 (s, 3H), 3.23 (m, 2H), 4.46 (s,2H), 7.14 (m, 2H), 7.12 (m, 1H), 7.56 (m, 4H).

Example 913-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-phenylbenzamide

To the solution of3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicacid (23 mg, 0.05 mmol) in CH₂Cl₂ (3 mL) were added aniline (0.005 mL,0.055 mmol), HATU (20 mg, 0.052 mmol) and diisopropyl ethyl amine (0.05mL, 0.3 mmol). The reaction mixture was stirred over night. The reactionmixture was diluted with CH₂Cl₂ (5 mL) and water (5 mL) and shaked. Thelayers were separated and the organic layer was washed with brine (8mL), dried over Na₂SO₄, filtered and concentrated. CombiFlashchromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) then providedthe title compound as a white solid (15 mg, 56%). LC-MS m/z 544 (M+H)⁺;¹H-NMR (MeOD) δ 2.43 (s, 6H), 2.70 (m, 2H), 3.48 (m, 2H), 4.52 (s, 2H),7.17 (m, 3H), 7.39 (m, 2H), 7.52 (m, 1H), 7.69 (m, 3H), 7.79 (d, 1H),8.08 (d, 1H), 8.15 (s, 1H).

Example 923-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-1,3-thiazol-2-ylbenzamide

To the solution of3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicacid (15 mg, 0.03 mmol) in CH₂Cl₂ (3 mL) were added 1,3-thiazol-2-amine(3.5 mg, 0.035 mmol), HATU (13 mg, 0.034 mmol) and diisopropyl ethylamine (0.05 mL, 0.3 mmol). The reaction mixture was stirred over night.The reaction mixture was diluted with CH₂Cl₂ (5 mL) and water (5 mL) andshaked. The layers were separated and the organic layer was washed withbrine (8 mL), dried over Na₂SO₄, filtered and concentrated. CombiFlashchromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) then providedthe title compound as a white solid (7 mg, 40%). LC-MS m/z 551 (M+H)⁺;¹H-NMR (MeOD) δ 2.22 (s, 6H), 2.46 (m, 2H), 3.16 (m, 2H), 4.51 (s, 2H),7.17 (m, 3H), 7.51 (m, 2H), 7.69 (m, 1H), 7.83 (d, 1H), 8.16 (d, 1H),8.23 (s, 1H).

Example 933-(8-(2,6-difluorophenyl)-2-{[-2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)benzamide

To the solution of3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicacid (15 mg, 0.03 mmol) in CH₂Cl₂ (3 mL) were added 4-flouroaniline(0.003 mL, 0.035 mmol), HATU (13 mg, 0.034 mmol) and diisopropyl ethylamine (0.05 mL, 0.3 mmol). The reaction mixture was stirred over night.The reaction mixture was diluted with CH₂Cl₂ (5 mL) and water (5 mL) andshaked. The layers were separated and the organic layer was washed withbrine (8 mL), dried over Na₂SO₄, filtered and concentrated. CombiFlashchromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) then providedthe title compound as a white solid (13 mg, 72%). LC-MS m/z 562 (M+H)⁺;¹H-NMR (MeOD) δ 2.81 (s, 6H), 3.21 (m, 2H), 3.59 (m, 2H), 4.53 (s, 2H),7.17 (m, 4H), 7.53 (m, 1H), 7.72 (m, 3H), 7.80 (d, 1H), 8.10 (d, 1H),8.16 (s, 1H).

Example 943-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-methylbenzamide

To the solution of3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicacid (15 mg, 0.03 mmol) in CH₂Cl₂ (3 mL) were added methylamine (2.0 Msoln. in THF, 0.018 mL, 0.036 mmol), HATU (13 mg, 0.034 mmol) anddiisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture wasstirred over night. The reaction mixture was diluted with CH₂Cl₂ (5 mL)and water (5 mL) and shaked. The layers were separated and the organiclayer was washed with brine (8 mL), dried over Na₂SO₄, filtered andconcentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOH[7]+NH₄OH[3]) then provided the title compound as awhite solid (10 mg, 65%). LC-MS m/z 482 (M+H)⁺; ¹H-NMR (MeOD) δ 2.16 (s,6H), 2.38 (m, 2H), 2.96 (s, 3H), 3.22 (m, 2H), 4.45 (s, 2H), 7.16 (m,2H), 7.50 (m, 1H), 7.64 (m, 1H), 7.74 (d, 1H), 7.95 (d, 1H), 8.00 (s,1H).

Example 953-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-propylbenzamide

To the solution of3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicacid (15 mg, 0.03 mmol) in CH₂Cl₂ (3 mL) were added propylamine (0.003mL, 0.035 mmol), HATU (13 mg, 0.034 mmol) and diisopropyl ethyl amine(0.05 mL, 0.3 mmol). The reaction mixture was stirred over night. Thereaction mixture was diluted with CH2C12 (5 mL) and water (5 mL) andshaked. The layers were separated and the organic layer was washed withbrine (8 mL), dried over Na₂SO₄, filtered and concentrated. CombiFlashchromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) then providedthe title compound as a white solid (5 mg, 31%). LC-MS m/z 510 (M+H)⁺;¹H-NMR (MeOD) δ 1.00 (t, 3H), 1.67 (m, 2H), 2.80 (s, 6H), 3.25 (m, 2H),3.40 (m, 2H), 3.62 (m, 2H), 4.52 (s, 2H), 7.19 (m, 1H), 7.53 (m, 1H),7.65 (m, 1H), 7.76 (d, 1H), 7.98 (d, 1H), 8.05 (s, 1H).

Example 964-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-1,3-thiazol-2-ylbenzamide96a)4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino{-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicacid

To a solution of5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)ethyl]-amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(150 mg, 0.39 mmol) in dioxane (12 mL)/water (4 mL) were added potassiumcarbonate (325 mg, 2.36 mmol), tetrakis(triphenylphosphine)palladium(0)(23 mg, 0.019 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (146 mg,0.59 mmol). The reaction mixture was bubbled with N₂ for 5 mins, thenmicrowaved at 150° C. for 30 mins. The reaction mixture wasconcentrated. To the concentrated mixture were added DMSO (2 mL), H₂O(0.5 mL) and AcOH (0.05 mL). Separation via a HPLC then provided thetitle compound as a white solid (142 mg, 77%). LC-MS m/z 469 (M+H)⁻.

96b)4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl[amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-1,3-thiazol-2-ylbenzamide

To the solution of the title compound from Example 96a (15 mg, 0.03mmol) in DMF (3 mL) were added 1,3-thiazol-2-amine (3.5 mg, 0.035 mmol),HATU (13 mg, 0.035 mmol) and diisopropyl ethyl amine (0.05 mL, 0.3mmol). The reaction mixture was stirred over night. The reaction mixturewas diluted with CH₂Cl₂ (5 mL) and water (5 mL) and shaked. The layerswere separated and the organic layer was washed with brine (8 mL), driedover Na₂SO₄, filtered and concentrated. CombiFlash chromatography(mobile phase DCM/DCM[90]+MeOH[7]+NH₄OH[3]) then provided the titlecompound as a white solid (7 mg, 40%). LC-MS m/z 551 (M+H)⁺; ¹H-NMR(MeOD) δ 2.83 (s, 6H), 3.15 (m, 2H), 3.51 (m, 2H), 4.52 (s, 2H), 7.17(m, 3H), 7.53 (m, 2H), 7.77 (m, 2H), 8.19 (m, 2H).

Example 974-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(1-methylethyl)benzamidetrifluoroacetate

To the solution of4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicacid (15 mg, 0.03 mmol) in CH₂Cl₂ (3 mL) were added isopropylamine(0.0085 mL, 0.1 mmol) and HATU (13 mg, 0.035 mmol). The reaction mixturewas stirred over night. The reaction mixture was concentrated.Separation via a HPLC with TFA then provided the title compound as awhite solid (5 mg, 31%). LC-MS m/z 510 (M+H)⁺; ¹H-NMR (MeOD) δ 1.29 (d,6H), 2.79 (s, 6H), 3.22 (m, 2H), 3.59 (m, 2H), 4.26 (m, 1H), 4.50 (s,2H), 7.17 (m, 2H), 7.54 (m, 1H), 7.67 (m, 2H), 7.99 (m, 2H).

Example 984-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-propylbenzamidetrifluoroacetate

To the solution of4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicacid (15 mg, 0.03 mmol) in CH₂Cl₂ (3 mL) were added propylamine (0.0082mL, 0.1 mmol) and HATU (13 mg, 0.035 mmol). The reaction mixture wasstirred over night. The reaction mixture was concentrated. Separationvia a HPLC with TFA then provided the title compound as a white solid (5mg, 31%). LC-MS m/z 510 (M+H)⁺; ¹H-NMR (MeOD) δ1.02 (t, 3H), 1.68 (m,2H), 2.79 (s, 6H), 3.22 (m, 2H), 3.59 (m, 2H), 4.50 (s, 2H), 7.17 (m,2H), 7.54 (m, 1H), 7.68 (m, 2H), 7.99 (m, 2H).

Example 994-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-phenylbenzamidetrifluoroacetate

To the solution of-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicacid (15 mg, 0.03 mmol) in CH₂Cl₂ (3 mL) were added aniline (0.0091 mL,0.1 mmol) and HATU (13 mg, 0.035 mmol). The reaction mixture was stirredover night. The reaction mixture was concentrated. Separation via a HPLCwith TFA then provided the title compound as a white solid (7 mg, 40%).LC-MS m/z 544 (M+H)⁺; ¹H-NMR (MeOD) δ 2.80 (s, 6H), 3.21 (m, 2H), 3.59(m, 2H), 4.53 (s, 2H), 7.18 (m, 3H), 7.40 (m, 2H), 7.52 (m, 1H), 7.72(m, 4H), 8.12 (m, 2H).

Example 1004-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)benzamidetrifluoroacetate

To the solution of-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicacid (15 mg, 0.03 mmol) in CH₂Cl₂ (3 mL) were added 4-flouroaniline(0.0096 mL, 0.1 mmol) and HATU (13 mg, 0.035 mmol). The reaction mixturewas stirred over night. The reaction mixture was concentrated.Separation via a HPLC with TFA then provided the title compound as awhite solid (7 mg, 39%). LC-MS m/z 562 (M+H)⁺; ¹H-NMR (MeOD) δ 2.80 (s,6H), 3.19 (m, 2H), 3.59 (m, 2H), 4.53 (s, 2H), 7.17 (m, 4H), 7.52 (m,1H), 7.72 (m, 4H), 8.12 (m, 2H).

Example 1014-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,N-dimethylbenzamidetrifluoroacetate

To the solution of-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicacid (20 mg, 0.043 mmol) in CH₂Cl₂ (2 mL) were added dimethylamine (2.0M soln. in THF, 0.064 mL, 0.13 mmol) and HATU (17.2 mg, 0.045 mmol). Thereaction mixture was stirred over night. The reaction mixture wasconcentrated. Separation via a HPLC with TFA then provided the titlecompound as a white solid (18 mg, 85%). LC-MS m/z 496 (M+H)⁺; ¹H-NMR(MeOD) δ 2.79 (s, 6H), 3.06 (s, 3H), 3.16 (s, 3H), 3.22 (m, 2H), 3.58(m, 2H), 4.50 (s, 2H), 7.17 (m, 2H), 7.54 (m, 1H), 7.61 (m, 2H), 7.71(m, 2H).

Example 1024-(8-(2,6-difluorophenyl)-2-{[-2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-methylbenzamidetrifluoroacetate

To the solution of-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicacid (20 mg, 0.043 mmol) in CH₂Cl₂ (2 mL) were added methylamine (2.0 Msoln. in THF, 0.064 mL, 0.13 mmol) and HATU (17.2 mg, 0.045 mmol). Thereaction mixture was stirred over night. The reaction mixture wasconcentrated. Separation via a HPLC with TFA then provided the titlecompound as a white solid (3 mg, 15%). LC-MS m/z 482 (M+H)⁺; ¹H-NMR(MeOD) δ 2.79 (s, 6H), 2.98 (s, 3H), 3.26 (m, 2H), 3.59 (m, 2H), 4.50(s, 2H), 7.17 (m, 2H), 7.53 (m, 1H), 7.68 (m, 2H), 7.99 (m, 2H).

Example 1034-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzamidetrifluoroacetate

To the solution of-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoicacid (20 mg, 0.043 mmol) in CH₂Cl₂ (2 mL) were added ammonia (2.0 Msoln. in propanol, 0.064 mL, 0.13 mmol) and HATU (17.2 mg, 0.045 mmol).The reaction mixture was stirred over night. The reaction mixture wasconcentrated. Separation via a HPLC with TFA then provided the titlecompound as a white solid (18 mg, 90%). LC-MS m/z 468 (M+H)⁺; ¹H-NMR(MeOD) δ 2.79 (s, 6H), 3.18 (m, 2H), 3.58 (m, 2H), 4.50 (s, 2H), 7.17(m, 2H), 7.53 (m, 1H), 7.71 (m, 2H), 8.05 (m, 2H).

Example 1044-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methyl-N-(1-methylethyl)benzamidetrifluoroacetate 104a)3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid

To a solution of 4-iodo-3-methylbenzoic acid (520 mg, 2.0 mmol) in DMF(8 mL) were added palladium acetate (23 mg, 0.10 mmol), potassiumacetate (590 mg, 6.0 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (560 mg, 2.2mmol). The reaction mixture was microwaved at 150° C. for 30 mins. Thereaction mixture was poured into water (25 mL), extracted withethylacetate (100 mL) while acetic acid (1 mL) was added. The organiclayer was washed with water (50 mL), brine (50 mL), dried with sodiumsulfate, filtered and concentrated. The residue was separated bycombiflash which provided the title compound as a white solid (460 mg,88%). LC-MS m/z 263 (M+H)⁺.

104b)4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methylbenzoicacid

To a solution of5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)ethyl]-amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(200 mg, 0.52 mmol) in dioxane (15 mL)/water (5 mL) were added potassiumcarbonate (433 mg, 3.14 mmol), tetrakis(triphenylphosphine)palladium(0)(31 mg, 0.027 mmol) and3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(205 mg, 0.78 mmol). The reaction mixture was bubbled with N₂ for 10mins, then microwaved at 150° C. for 30 mins. The reaction mixture wasconcentrated. To the concentrated mixture were added DMSO (2 mL), H₂O(0.5 mL) and AcOH (0.05 mL). Gilson with TFA provided the title compoundas a white solid (310 mg, 99%). LC-MS m/z 483 (M+H)⁺.

104c)4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

To the solution of the title compound from Example 104b (25 mg, 0.052mmol) in CH₂Cl₂ (2 mL) were added isopropylamine (0.022 mL, 0.25 mmol)and HBTU (21 mg, 0.055 mmol). The reaction mixture was stirred overnight. The reaction mixture was concentrated. Separation via a HPLC withTFAthen provided the title compound as a white solid (17 mg, 63%). LC-MSm/z 524 (M+H)⁺; ¹H-NMR (MeOD) δ 1.29 (d, 6H), 2.34 (s, 3H), 2.76 (s,6H), 3.16 (m, 2H), 3.55 (m, 2H), 4.15 (s, 2H), 4.25 (m, 1H), 7.21 (m,2H), 7.36 (m, 1H), 7.55 (m, 1H), 7.78 (d, 1H), 7.84 (s, 1H).

Example 1054-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methyl-N-propylbenzamidetrifluoroacetate

To the solution of4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methylbenzoicacid (25 mg, 0.052 mmol) in CH₂Cl₂ (2 mL) were added propylamine (0.021mL, 0.25 mmol) and HBTU (21 mg, 0.055 mmol). The reaction mixture wasstirred over night. The reaction mixture was concentrated. Separationvia a HPLC with TFA then provided the title compound as a white solid (7mg, 26%). LC-MS m/z 524 (M+H)⁺; ¹H-NMR (MeOD) δ 1.01 (t, 3H), 1.67 (m,2H), 2.33 (s, 3H), 2.76 (s, 6H), 3.16 (m, 2H), 3.55 (m, 2H), 4.15 (s,2H), 7.18 (m, 2H), 7.36 (m, 1H), 7.55 (m, 1H), 7.78 (d, 1H), 7.84 (s,1H).

Example 1064-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methyl-N-phenylbenzamidetrifluoroacetate

To the solution of4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methylbenzoicacid (25 mg, 0.052 mmol) in CH₂Cl₂ (2 mL) were added aniline (0.024 mL,0.25 mmol) and HBTU (21 mg, 0.055 mmol). The reaction mixture wasstirred over night. The reaction mixture was concentrated. Separationvia a HPLC with TFA then provided the title compound as a white solid(23 mg, 79%). LC-MS m/z 558 (M+H)⁺; ¹H-NMR (MeOD) δ 2.38 (s, 3H), 2.77(s, 6H), 3.16 (m, 2H), 3.55 (m, 2H), 4.17 (s, 2H), 7.21 (m, 3H), 7.42(m, 3H), 7.55 (m, 1H), 7.72 (m, 2H), 7.89 (m, 1H), 7.97 (s, 1H).

Example 1074-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-3-methylbenzamidetrifluoroacetate

To the solution of4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methylbenzoicacid (25 mg, 0.052 mmol) in CH₂Cl₂ (2 mL) were added 4-flouroaniline(0.025 mL, 0.25 mmol) and HBTU (21 mg, 0.055 mmol). The reaction mixturewas stirred over night. The reaction mixture was concentrated.Separation via a HPLC with TFA then provided the title compound as awhite solid (22 mg, 74%). LC-MS m/z 576 (M+H)⁺; ¹H-NMR (MeOD) δ 2.37 (s,3H), 2.77 (s, 6H), 3.16 (m, 2H), 3.55 (m, 2H), 4.17 (s, 2H), 7.16 (m,4H), 7.42 (m, 1H), 7.55 (m, 1H), 7.72 (m, 2H), 7.89 (m, 1H), 7.97 (s,1H).

Example 1084-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,N,3-trimethylbenzamidetrifluoroacetate

To the solution of4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methylbenzoicacid (25 mg, 0.052 mmol) in CH₂Cl₂ (2 mL) were added dimethylamine (2.0M soln. in THF, 0.13 mL, 0.26 mmol) and HBTU (21 mg, 0.055 mmol). Thereaction mixture was stirred over night. The reaction mixture wasconcentrated. Separation via a HPLC with TFA then provided the titlecompound as a white solid (19 mg, 72%). LC-MS m/z 510 (M+H)⁺; ¹H-NMR(MeOD) δ 2.32 (s, 3H), 2.77 (s, 6H), 3.06 (s, 3H), 3.15 (m, 5H), 3.55(m, 2H), 4.17 (s, 2H), 7.19 (m, 2H), 7.37 (m, 2H), 7.46 (s, 1H), 7.55(m, 1H).

Example 1094-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,3-dimethylbenzamidetrifluoroacetate

To the solution of4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methylbenzoicacid (25 mg, 0.052 mmol) in CH₂Cl₂ (2 mL) were added methylamine (2.0 Msoln. in THF, 0.13 mL, 0.26 mmol) and HBTU (21 mg, 0.055 mmol). Thereaction mixture was stirred over night. The reaction mixture wasconcentrated. Separation via a HPLC with TFA then provided the titlecompound as a white solid (3 mg, 12%). LC-MS m/z 496 (M+H)⁺; ¹H-NMR(MeOD) δ 2.33 (s, 3H), 2.76 (s, 6H), 2.96 (s, 3H), 3.15 (m, 2H), 3.55(m, 2H), 4.15 (s, 2H), 7.18 (m, 2H), 7.36 (m, 1H), 7.55 (m, 1H), 7.76(m, 1H), 7.83 (s, 1H).

Example 1104-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methylbenzamidetrifluoroacetate

To the solution of4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methylbenzoicacid (25 mg, 0.052 mmol) in CH₂Cl₂ (2 mL) were added ammonia (2.0 Msoln. in propanol, 0.13 mL, 0.26 mmol) and HBTU (21 mg, 0.055 mmol). Thereaction mixture was stirred over night. The reaction mixture wasconcentrated. Separation via a HPLC with TFA then provided the titlecompound as a white solid (15 mg, 60%). LC-MS m/z 482 (M+H)⁺; ¹H-NMR(MeOD) δ 2.33 (s, 3H), 2.76 (s, 6H), 3.15 (m, 2H), 3.55 (m, 2H), 4.15(s, 2H), 7.19 (m, 2H), 7.36 (m, 1H), 7.55 (m, 1H), 7.84 (m, 1H), 7.91(s, 1H).

Example 1113-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methyl-N-(1-methylethyl)benzamide111a) 1,1-dimethylethyl3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzoate

To a solution of5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)ethyl]amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(200 mg, 0.52 mmol) in dioxane (15 mL)/water (5 mL) were added potassiumcarbonate (433 mg, 3.14 mmol), tetrakis(triphenylphosphine)palladium(0)(31 mg, 0.027 mmol) and(5-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-2-methylphenyl)boronicacid (159 mg, 0.63 mmol). The reaction mixture was bubbled with N₂ for10 mins, then microwaved at 150° C. for 30 mins. The reaction mixturewas concentrated. To the concentrated mixture were added DMSO (2 mL),H₂O (0.5 mL) and AcOH (0.05 mL). Separation via a HPLC then provided thetitle compound as a white solid (270 mg, 88%). LC-MS m/z 587 (M+H)⁺.

111b)3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzoicacid

To a solution of the title compound from Example 111a (260 mg, 0.45mmol) in CH₂Cl₂ (1 mL) were added TFA (0.45 mL, 5.84 mmol) andtriethylsilane (0.18 mL, 1.12 mmol). The reaction mixture was stirredovernight. The reaction mixture was concentrated. Separation via a HPLCthen provided the title compound as a white solid (260 mg, 96%). LC-MSm/z 501 (M+H)⁺.

111c)3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methyl-N-(1-methylethyl)benzamide

To the solution of the title compound from Example 111b (25 mg, 0.05mmol) in CH₂Cl₂ (2 mL) were added isopropylamine (0.021 mL, 0.25 mmol)and HBTU (20 mg, 0.053 mmol). The reaction mixture was stirred overnight. The reaction mixture was concentrated. Separation via a HPLC withTFA followed by treatment with t-amino SPE cartridge then provided thetitle compound as a white solid (9 mg, 33%). LC-MS m/z 542 (M+H)⁺;¹H-NMR (MeOD) δ 1.27 (d, 6H), 2.40 (s, 3H), 2.78 (s, 6H), 3.15 (m, 2H),3.55 (m, 2H), 4.22 (m, 3H), 7.18 (m, 2H), 7.57 (m, 2H), 7.71 (m, 1H).

Example 1123-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methyl-N-phenylbenzamide

To the solution of3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimidin[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzoicacid (25 mg, 0.05 mmol) in CH₂Cl₂ (2 mL) were added aniline (0.025 mL,0.25 mmol) and HBTU (20 mg, 0.053 mmol). The reaction mixture wasstirred over night. The reaction mixture was concentrated. Separationvia a HPLC with TFA followed by treatment with t-amino SPE cartridgethen provided the title compound as a white solid (10 mg, 35%). LC-MSm/z 576 (M+H); ¹H-NMR (MeOD) δ 2.27 (s, 3H), 2.79 (s, 6H), 3.15 (m, 2H),3.55 (m, 2H), 4.21 (s, 2H), 7.19 (m, 3H), 7.39 (m, 2H), 7.54 (m, 1H),7.71 (m, 3H), 7.86 (m, 1H).

Example 1133-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-N,N,4-trimethylbenzamide

To the solution of3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzoicacid (25 mg, 0.05 mmol) in CH₂Cl₂ (2 mL) were added dimethylamine (2.0 Msoln. in THF, 0.13 mL, 0.26 mmol), triethylamine (0.05 mL, 0.36 mmol)and HBTU (20 mg, 0.053 mmol). The reaction mixture was stirred overnight. The reaction mixture was concentrated. Separation via a HPLC withTFA followed by treatment with t-amino SPE cartridge then provided thetitle compound as a white solid (15 mg, 57%). LC-MS m/z 528 (M+H)⁺;¹H-NMR (MeOD) δ 2.23 (s, 3H), 2.78 (s, 6H), 3.06 (s, 3H), 3.15 (m, 5H),3.55 (m, 2H), 4.22 (s, 2H), 7.19 (m, 3H), 7.34 (m, 1H), 7.56 (m, 1H).

Example 1143-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-N,4-dimethylbenzamide

To the solution of3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzoicacid (25 mg, 0.05 mmol) in CH₂Cl₂ (2 mL) were added methylamine (2.0 Msoln. in THF, 0.13 mL, 0.26 mmol), triethylamine (0.05 mL, 0.36 mmol)and HBTU (20 mg, 0.053 mmol). The reaction mixture was stirred overnight. The reaction mixture was concentrated. Separation via a HPLC withTFA followed by treatment with t-amino SPE cartridge then provided thetitle compound as a white solid (14 mg, 54%). LC-MS m/z 514 (M+H)⁺;

¹H-NMR (MeOD) δ 2.24 (s, 3H), 2.78 (s, 6H), 2.94 (s, 3H), 3.15 (m, 2H),3.55 (m, 2H), 4.22 (s, 2H), 7.18 (m, 2H), 7.56 (m, 2H), 7.39 (m, 1H).

Example 1153-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino{-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-N-(4-fluorophenyl)-4-methylbenzamide

To the solution of3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzoicacid (25 mg, 0.05 mmol) in CH₂Cl₂ (2 mL) were added 4-flouroaniline(0.025 mL, 0.25 mmol), triethylamine (0.05 mL, 0.36 mmol) and HBTU (20mg, 0.053 mmol). The reaction mixture was stirred over night. Thereaction mixture was concentrated. Separation via a HPLC with TFAfollowed by treatment with t-amino SPE cartridge then provided the titlecompound as a white solid (26 mg, 88%). LC-MS m/z 594 (M+H)⁺; ¹H-NMR(MeOD) δ 2.27 (s, 3H), 2.79 (s, 6H), 3.16 (m, 2H), 3.55 (m, 2H), 4.21(s, 2H), 7.15 (m, 4H), 7.54 (m, 1H), 7.71 (m, 3H), 7.85 (m, 1H).

Example 1163-{8-(2,6-difluorophenyl)-2-[{3-[[3-(dimethylamino)propyl]-(methyl)amino]propyl}(methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide

To a solution of3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide(20 mg, 0.04 mmol) in CH₂Cl₂ (1 mL) were addedN-[3-(dimethylamino)propyl]-N,N′-dimethyl-1,3-propanediamine (0.004 mL,0.02 mmol) and triethylamine (0.05 mL, 0.36 mmol). The resultantsolution was stirred at room temperature over night. The reactionmixture was concentrated. Separation via a HPLC followed by treatmentwith t-amino SPE cartridge then provided the title compound as a whitesolid (7 mg, 29%). LC-MS m/z 609 (M+H)⁺; ¹H-NMR (MeOD) δ 1.29 (d, 6H),1.95 (m, 4H), 2.33 (s, 3H), 2.75 (s, 3H), 2.78 (s, 3H), 2.92 (s, 3H),3.17 (m, 6H), 3.50 (m, 2H), 4.15 (s, 2H), 4.23 (m, 1H), 7.19 (m, 2H),7.48 (d, 1H), 7.55 (m, 1H), 7.71 (s, 1H), 7.86 (d, 1H).

Example 1173-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzoicacid

To the solution of5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)ethyl]amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(191 mg, 0.50 mmol) in dioxane (15 mL) and water (5 mL) were added4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(197 mg, 0.75 mmol), K₂CO₃ (415 mg, 3.0 mmol) andtetrakis(triphenyl-phosphine)palladium(0) (23 mg, 0.025 mmol). Thereaction mixture was heated to 150° C. for 15 minutes with microwave.The reaction mixture was concentrated to dry then was added DMSO (2 mL),water (0.5 mL) and HOAc (1 drop). The solution was filtered and appliedto the reverse phase HPLC to afford the titled compound 0.24 g(quantitative). LC-MS m/z 483 (M+H)⁺; ¹H-NMR (MeOD) 2.36 (s, 3H), 2.76(s, 6H), 3.16 (s, 2H), 3.56 (s, 2H), 4.13 (s, 2H), 7.21 (m, 1H), 7.53(m, 2H), 7.95 (s, 1H), 8.09 (d, J=7.6 Hz, 1H).

Example 1183-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide118a)3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide

To the solution of3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoicacid (1.41 g, 3.19 mmol) in DMF (50 mL) was added 2-aminothiazole (479mg, 4.78 mmol), HBTU (1.33 g, 3.51 mmol) and Et₃N (0.90 mL, 6.38 mmol).The reaction mixture was stirred at room temperature for 18 hours beforewas concentrated and applied to flash chromatography to afford thetitled compound 0.99 g (60%). LC-MS m/z 525 (M+H)⁺.

118b) 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide

To the solution of3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide(262 mg, 0.50 mmol) in dichloromethane (10 mL) was added mCPBA (116 mg,0.75 mmol). The reaction mixture was stirred at room temperature for 10minutes. Then the reaction mixture was applied to flash chromatographyto afford the titled compound 256 mg (95%). LC-MS m/z 541 (M+H)⁺.

118c)3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide

To the solution of348-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide(30 mg, 0.055 mmol) in dichloromethane (3.0 mL) were addedN,N-dimethyl-1,2-ethanediamine (12.2 μL, 0.11 mmol) and triethylamine(15.6 μL, 0.11 mmol). The reaction mixture was stirred at roomtemperature for 16 hours then was concentrated, redissolved in DMSO (0.5mL), filtered and applied to the reverse phase HPLC to afford the titledcompound 16.9 mg (54%). LC-MS m/z 565 (M+H)⁺; ¹H-NMR (MeOD) 2.20 (s, 3H), 2.33 (m, 7H), 2.81 (s, 2H), 3.26 (m, 1H), 4.13 (m, 1H), 4.43 (s,1H), 7.17 (m, 3H), 7.50 (m, 3H), 8.01 (m, 2H).

Example 1193-(8-(2,6-difluorophenyl)-2-{[3-(dimethylamino)propyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide

The title compound was prepared by following the procedure in Example118c except N,N,N′-trimethyl-1,3-propanediamine was used in thedisplacement (yield: 86%). LC-MS m/z 579 (M+H)⁺; ¹H-NMR (MeOD) 1.83 (m,2H), 2.37 (s, 3H), 2.78 (s, 6H), 3.02 (s, br, 2H), 3.27 (m, 2H), 4.17(m, 2H), 7.19 (m, 3H), 7.55 (m, 3H), 7.92 (s, 1H), 8.08 (m, 1H).

Example 1203-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide

The title compound was prepared by following the procedure in Example118c except N,N-diethyl-1,3-propanediamine was used in the displacement(yield: 64%). LC-MS m/z 607 (M+H)⁺; ¹H-NMR (MeOD) 1.14 (t, J=7.6 Hz,6H), 1.70 (m, 2H), 2.34 (s, 3H), 2.76 (m, 2H), 2.90 (m, 4H), 3.18 (m,2H), 4.11 (m, 2H), 7.18 (m, 3H), 7.53 (s, 3H), 7.89 (s, 1H), 8.04 (d,J=7.2 Hz, 1H).

Example 1213-[2-{[3-(dibutylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide

The title compound was prepared by following the procedure in Example118c except N,N-dibutyl-1,3-propanediamine was used in the displacement(yield: 99%). LC-MS m/z 663 (M+H)⁺; ¹H-NMR (MeOD) 0.97 (m, 6H), 1.38 (m,4H), 1.59 (m, 4H), 1.81 (m, 2H), 2.35 (s, 3H), 3.05 (m, 6H), 3.23 (m,2H), 4.11 (m, 2H), 7.18 (m, 3H), 7.53 (m, 3H), 7.89 (s, 1H), 8.05 (d,J=7.6 Hz, 1H).

Example 1223-[8-(2,6-difluorophenyl)-2-({2-[(1-methylethyl)amino]ethyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide

The title compound was prepared by following the procedure in Example118c except N-(1-methylethyl)-1,2-ethanediamine was used in thedisplacement (yield: 31%). LC-MS m/z 579 (M+H)⁺; ¹H-NMR (MeOD) 1.16 (d,J=6.4 Hz, 6H), 2.37 (s, 3H), 3.02 (s, 2H), 3.21 (m, 1H), 3.46 (m, 2H),4.19 (m, 2H), 7.18 (m, 3H), 7.53 (d, J=3.6 Hz, 2H), 7.59 (d, J=8.4 Hz,1H), 7.92 (s, 1H), 8.08 (m, 1H).

Example 1233-[8-(2,6-difluorophenyl)-2-({3-[1-methylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide

The title compound was prepared by following the procedure in Example118c except N-(1-methylethyl)-1,3-propanediamine was used in thedisplacement (yield: 71%). LC-MS m/z 593 (M+H)⁺; ¹H-NMR (MeOD) 1.23 (m,6H), 1.78 (m, 2H), 2.36 (s, 3H), 2.91 (s, 2H), 3.27 (m, 3H), 4.15 (m,2H), 7.18 (m, 3H), 7.53 (d, J=3.6 Hz, 2H), 7.56 (d, J=8.4 Hz, 1H), 7.91(s, 1H), 8.08 (m, 1H).

Example 1243-{8-(2,6-difluorophenyl)-2-[[3-(dimethylamino)propyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-1,3-thiazol-2-ylbenzamide

The title compound was prepared by following the procedure in Example118c except N,N,N-trimethyl-1,3-propanediamine was used in thedisplacement (yield: 35%). LC-MS m/z 593 (M+H)⁺; ¹H-NMR (MeOD) 1.62 (m,2H), 2.09 (m, 3H), 2.20 (s, 6H), 2.36 (s, 3H), 2.98 (m, 3H), 3.38 (m,1H), 4.17 (m, 2H), 7.17 (m, 3H), 7.53 (m, 3H), 7.92 (s, 1H), 8.05 (d,J=8.0 Hz, 1H).

Example 1253-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(2,2-dimethylpropyl)-4-methylbenzamide

To the solution of3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzoicacid (30 mg, 0.062 mmol) in dichloromethane (2.0 mL) and DMF (0.5 mL)were added (2,2-dimethylpropyl)amine (10.9 μL, 0.093 mmol), HBTU (25.6mg, 0.068 mmol) and triethylamine (35.0 μL, 0.25 mmol). The reactionmixture was stirred at room temperature for 16 hours then was applied toHPLC to afford the titled compound 14.9 mg (44%). LC-MS m/z 552 (M+H)⁺;¹H-NMR (MeOD) 0.99 (s, 9H), 2.33 (s, 3H), 2.76 (s, 6H), 3.15 (s, 2H),3.24 (s, 2H), 3.54 (m, 2H), 4.16 (m, 2H), 7.18 (m, 2H), 7.51 (m, 2H),7.72 (s, 1H), 7.89 (m, 1H).

Example 126 Methyl3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzoate

The title compound was prepared by following the procedure in Example125 except methanol was used in the coupling reaction (yield: 44%).LC-MS m/z 497 (M+H)⁺; ¹H-NMR (MeOD) 2.34 (s, 3H), 2.76 (s, 6H), 3.15 (s,2H), 3.54 (m, 2H), 3.93 (s, 3H), 4.12 (m, 2H), 7.18 (m, 2H), 7.52 (m,2H), 7.89 (s, 1H), 8.04 (m, 1H).

Example 1273-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-[4-(methylthio)phenyl]benzamide

The title compound was prepared by following the procedure in Example125 except [4-(methylthio)phenyl]amine was used in the coupling reaction(yield: 36%). LC-MS m/z 604 (M+H)⁺; ¹H-NMR (MeOD) 2.24 (s, 6H), 2.35 (s,3H), 2.49 (m, 5H), 3.26 (m, 1H), 3.37 (m, 1H), 4.16 (m, 2H), 7.15 (t,J=8.4 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.53 (m, 2H), 7.66 (d, J=8.8 Hz,2H), 7.82 (s, 1H), 7.98 (m, 1H).

Example 1283-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-[(2R)-2-hydroxypropyl]-4-methylbenzamide

The title compound was prepared by following the procedure in Example125 except (2R)-1-amino-2-propanol was used in the coupling reaction(yield: 15%). LC-MS m/z 540 (M+H)⁺; ¹H-NMR (MeOD) 1.22 (d, J=6.4 Hz,3H), 2.32 (s, 3H), 2.51 (m, 6H), 2.83 (s, 2H), 3.43 (m, 4H), 3.97 (m,1H), 4.14 (m, 2H), 7.15 (t, J=8.4 Hz, 2H), 7.53 (m, 2H), 7.72 (s, 1H),7.88 (m, 1H).

Example 1293-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-[(2S)-2-hydroxypropyl]-4-methylbenzamide

The title compound was prepared by following the procedure in Example125 except (2S)-1-amino-2-propanol was used in the coupling reaction(yield: 37%). LC-MS m/z 540 (M+H)⁺; ¹H-NMR (MeOD) 1.22 (d, J=6.4 Hz,3H), 2.32 (s, 3H), 2.71 (s, 6H), 3.08 (s, 2H), 3.43 (m, 4H), 3.98 (m,1H), 4.13 (m, 2H), 7.17 (t, J=8.4 Hz, 2H), 7.49 (m, 2H), 7.72 (s, 1H),7.88 (m, 1H).

Example 1303-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-1,3-thiazol-2-ylbenzamidetrifluoroacetate

The title compound was prepared by following the procedure in Example118c except (1H-imidazol-2-ylmethyl)amine dihydrochloride was used inthe displacement and HPLC with TFA (yield: 18%). LC-MS m/z 574 (M+H)⁺;¹H-NMR (MeOD) 2.29 (m, 5H), 4.20 (m, 3H), 4.57 (m, 3H), 7.09 (m, 2H),7.22 (m, 1H), 7.48 (m, 5H), 7.90 (s, 1H), 8.08 (d, J=8.0 Hz, 1H).

Example 1313-{8-(2,6-difluorophenyl)-2-[[2-(dimethylamino)ethyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-1,3-thiazol-2-ylbenzamidetrifluoroacetate

The title compound was prepared by following the procedure in Example118c except N,N,N′-trimethyl-1,2-ethanediamine was used in thedisplacement and HPLC with TFA (yield: 49%). LC-MS m/z 579 (M+H)⁺;¹H-NMR (MeOD) 2.37 (s, 3H), 2.75 (s, 6H), 2.97 (s, 3H), 3.28 (s, 2H),3.82 (m, 2H), 4.23 (m, 2H), 7.23 (m, 3H), 7.58 (m, 3H), 7.94 (s, 1H),8.11 (m, 1H).

Example 1323-{8-(2,6-difluorophenyl)-2-[(2,2-dimethylpropyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-1,3-thiazol-2-ylbenzamidetrifluoroacetate

The title compound was prepared by following the procedure in Example118c except (2,2-dimethylpropyl)amine was used in the displacement andHPLC with TFA (yield: 32%). LC-MS m/z 564 (M+H)⁺; ¹H-NMR (MeOD) 0.76 (s,9H), 2.42 (s, 3H), 3.00 (s, 2H), 4.21 (m, 2H), 7.23 (m, 3H), 7.55 (d,J=3.8 Hz, 1H), 7.64 (m, 2H), 8.07 (s, 1H), 8.16 (d, J=8.0 Hz, 1H).

Example 1333-(8-(2,6-difluorophenyl)-2-{[(2R)-2-hydroxypropyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamidetrifluoroacetate

The title compound was prepared by following the procedure in Example118c except (2R)-1-amino-2-propanol was used in the displacement andHPLC with TFA (yield: 49%). LC-MS m/z 552 (M+H)⁺; ¹H-NMR (MeOD) 0.97 (m,3H), 2.43 (s, 3H), 3.00 (s, br, 2H), 3.19 (s, br, 2H), 3.76 (m, 1H),4.23 (m, 2H), 7.22 (m, 3H), 7.56 (m, 2H), 7.66 (d, J=8.0 Hz, 1H), 8.06(s, 1H), 8.18 (d, J=8.0 Hz, 1H).

Example 1343-(8-(2,6-difluorophenyl)-2-{[(2S)-2-hydroxypropyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-1,3-thiazol-2-ylbenzamide

The title compound was prepared by following the procedure in Example118c except (2S)-1-amino-2-propanol was used in the displacement (yield:27%). LC-MS m/z 552 (M+H)⁺; ¹H-NMR (MeOD) 0.97 (m, 3H), 2.43 (s, 3H),2.99 (s, br, 2H), 3.18 (s, br, 2H), 3.76 (m, 1H), 4.22 (m, 2H), 7.22 (m,3H), 7.55 (m, 2H), 7.66 (d, J=8.0 Hz, 1H), 8.05 (s, 1H), 8.18 (d, J=7.4Hz, 1H).

Example 1353-[8-(2,6-difluorophenyl)-2-({2-[2-(methyloxy)phenyl]ethyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamidetrifluoroacetate

The title compound was prepared by following the procedure in Example118c except 2-[2-(methyloxy)phenyl]ethanamine was used in thedisplacement and HPLC with TFA (yield: 33%). LC-MS m/z 628 (M+H)⁺;¹H-NMR (MeOD) 2.38 (s, 3H), 2.70 (s, br, 2H), 3.30 (m, 2H), 3.77 (s,3H), 4.16 (m, 2H), 6.89 (m, 3H), 7.18 (m, 4H), 7.57 (m, 3H), 7.98 (s,1H), 8.12 (d, J=8.0 Hz, 1H).

Example 1363-[8-(2,6-difluorophenyl)-7-oxo-2-(propylamino)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide

The title compound was prepared by following the procedure in Example118c except propyl amine was used in the displacement (yield: 29%).LC-MS m/z 536 (M+H)⁺; ¹H-NMR (MeOD) 0.77 (s, 3H), 1.45 (m, 2H), 2.44 (s,3H), 3.09 (s, 2H), 4.23 (m, 2H), 7.23 (m, 3H), 7.60 (m, 2H), 7.68 (m,1H), 8.08 (s, 1H), 8.20 (d, J=8.0 Hz, 1H).

Example 1373-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-phenylbenzamide

The title compound was prepared by following the procedure in Example125 except aniline was used in the amide coupling reaction (yield: 45%).LC-MS m/z 558 (M+H)⁺; ¹H-NMR (MeOD) 2.36 (s, 3H), 2.77 (s, 6H), 3.15 (s,2H), 3.55 (m, 2H), 4.20 (m, 2H), 7.18 (m, 3H), 7.38 (m, 2H), 7.56 (m,2H), 7.71 (m, 2H), 7.84 (s, 1H), 8.01 (d, J=8.0 Hz, 1H).

Example 138N-(3,4-difluorophenyl)-3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)-ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzamide

The title compound was prepared by following the procedure in Example125 except 3,4-difluoro aniline was used in the amide coupling reaction(yield: 15%). LC-MS m/z 594 (M+H)⁺; ¹H-NMR (MeOD) 2.36 (s, 3H), 2.77 (s,6H), 3.16 (s, 2H), 3.55 (m, 2H), 4.19 (m, 2H), 7.24 (m, 3H), 7.50 (m,3H), 7.86 (m, 2H), 8.00 (m, 1H).

Example 1393-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-3-pyridinylbenzamide

The title compound was prepared by following the procedure in Example125 except 3-pyridinamine was used in the amide coupling reaction(yield: 6%). LC-MS m/z 559 (M+H)⁺; ¹H-NMR (MeOD) 2.14 (s, 6H), 2.35 (m,5H), 3.24 (m, 2H), 4.14 (m, 2H), 7.15 (m, 2H), 7.50 (m, 3H), 7.87 (s,1H), 8.01 (m, 1H), 8.30 (m, 2H), 8.92 (s, 1H).

Example 1403-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-[6-(methyloxy)-3-pyridinyl]benzamide

The title compound was prepared by following the procedure in Example125 except 6-(methyloxy)-3-pyridinamine was used in the amide couplingreaction (yield: 65%). LC-MS m/z 589 (M+H)⁺; ¹H-NMR (MeOD) 2.12 (s, 6H),2.33 (m, 5H), 3.21 (m, 2H), 3.92 (s, 3H), 4.11 (m, 2H), 6.83 (d, J=8.8Hz, 1H), 7.14 (m, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.82 (s, 1H), 7.98 (m,2H), 8.44 (s, 1H).

Example 1413-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-ethylbenzoicacid

The title compound was prepared by following the procedure in Example117 except 3-(dihydroxyboranyl)-4-ethylbenzoic acid was used in thecoupling reaction (yield: 38%). LC-MS m/z 497 (M+H)⁺; ¹H-NMR (MeOD) 1.22(t, J=7.6 Hz, 3H), 2.68 (s, 2H), 2.77 (s, 6H), 3.16 (m, 2H), 3.53 (m,2H), 4.13 (m, 2H), 7.18 (m, 2H), 7.55 (m, 2H), 7.86 (s, 1H), 8.10 (m1H).

Example 1423-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-ethyl-N-(4-fluorophenyl)benzamidetrifluoroacetate

The title compound was prepared by following the procedure in Example125 except3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-ethylbenzoicacid was used as the acid and 4-fluoroaniline was used as the amine foramide coupling and HPLC with TFA (yield: 56%). LC-MS m/z 590 (M+H)⁺;¹H-NMR (MeOD) 1.22 (t, J=7.6 Hz, 3H), 2.69 (s, 2H), 2.77 (s, 6H), 3.15(m, 2H), 3.54 (m, 2H), 4.13 (m, 2H), 7.15 (m, 4H), 7.53 (m, 1H), 7.60(d, J=8.0 Hz, 1H), 7.72 (m, 2H), 7.80 (s, 1H), 8.05 (m 1H).

Example 143N-(3,4-difluorophenyl)-3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)-ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-ethylbenzamidetrifluoroacetate

The title compound was prepared by following the procedure in Example142 except 3,4-difluoroaniline was used in the amide coupling reactionand HPLC with TFA (yield: 54%). LC-MS m/z 608 (M+H)⁺; ¹H-NMR (MeOD) 1.24(t, J=7.6 Hz, 3H), 2.69 (s, 2H), 2.77 (s, 6H), 3.15 (m, 2H), 3.54 (m,2H), 4.18 (m, 2H), 7.24 (m, 3H), 7.54 (m, 3H), 7.85 (m, 2H), 8.05 (m1H).

Example 1443-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-ethyl-N-1,3-thiazol-2-ylbenzamidetrilfluoroacetate

The title compound was prepared by following the procedure in Example142 except 1,3-thiazol-2-amine was used in the amide coupling reactionand HPLC with TFA (yield: 43%). LC-MS m/z 579 (M+H)⁺; ¹H-NMR (MeOD) 1.25(t, J=7.6 Hz, 3H), 2.71 (s, 2H), 2.77 (s, 6H), 3.16 (m, 2H), 3.56 (m,2H), 4.18 (m, 2H), 7.20 (m, 3H), 7.55 (m, 2H), 7.66 (m, 1H), 7.90 (s,1H), 8.14 (m 1H).

Example 145N-1,3-benzodioxol-5-yl-3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)-ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzamidetrifluoroacetate

Prepared following General Procedure for HATU Couplings. Reversed-phaseHPLC (10-90% gradient of acetonitrile in water with 0.1% TFA) providedthe title compound 4.9 mg (23%). LC-MS m/z 602 (M+H)⁺.

Example 1463-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-ethylbenzamide

The title compound was prepared by following the procedure in Example142 except ammonia was used in the amide coupling reaction and HPLCwithout TFA (yield: 64%). LC-MS m/z 496 (M+H)⁺; ¹H-NMR (MeOD) 1.23 (m,3H), 2.13 (s, 6H), 2.35 (m, 2H), 2.66 (m, 2H), 3.26 (m, 2H), 4.12 (m,2H), 7.15 (m, 2H), 7.51 (m, 2H), 7.73 (s, 1H), 7.94 (m 1H).

Example 1471,1-dimethylethyl{1-[8-(2,6-difluorophenyl)-4-(2-methyl-5-{[(phenylmethyl)amino]carbonyl}phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]-4-piperidinyl}methylcarbamate

Compound3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide(0.0811 g, 0.144 mmol) was dissolved in CH₂Cl₂ (5 mL) and1,1-dimethylethyl methyl(4-piperidinyl)carbamate (0.0394 g, 0.18 mmol)and triethylamine (0.029 g, 0.288 mmol) were added. The reaction mixturewas stirred for 4 days. Additional 1,1-dimethylethylmethyl(4-piperidinyl)carbamate (0.0788 g, 0.36 mmol) and triethylamine(0.058 g, 0.576 mmol) were added and the mixture was stirred under argonat room temperature for an additional 7 days. The solvents were pumpedoff in vacuo, and the residue taken up in EtOAc and washed with 1 NNaOH, brine, dried over anhydrous Na₂SO₄ filtered and evaporated. Theresidue was flash chromatographed on silica gel (20 g) eluted with 0-70%EtOAc/hexane. Some impurities remained, so the material wasrechromatographed on silica gel (20 g) eluted with 0-50% EtOAc/hexane togive the title compound as a white amorphous solid. mp (dec) 146-150° C.LC-MS m/z 698 (M+H)⁺, 2.66 min (ret time).

Example 1483-[8-(2,6-difluorophenyl)-2-(4-methyl-1-piperazinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide

The3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide(0.056 g, 0.1 mmol) was dissolved in THF (5 mL) and 1-methylpiperazine(0.0303 g, 0.3 mmol) was added. The reaction was stirred for 72 h. Thesolvents were pumped off in vacuo, and the residue taken up in EtOAc andwashed with 1 N NaOH, brine, dried over anhydrous Na₂SO₄ filtered andevaporated. The residue was flash chromatographed on silica gel (20 g)eluted with 6:0.1:0.01 to 6:0.3:0.03, CH₂Cl₂:ethanol:NH₄OH to give thetitle compound as a white amorphous solid. mp 164-168° C. LC-MS m/z 584(M+H)⁺, 1.85 min (ret time).

Example 1493-[8-(2,6-difluorophenyl)-2-(4-methyl-1-piperazinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N,4-trimethylbenzamide149a)3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N,4-trimethylbenzamide

4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1g, 3.8 mmoles) was taken up in CH₂Cl₂ (200 mL) and was treated withoxalyl chloride (0.44 mL, 5 mmol) and DMF (1 drop). One hour after gasevolution had ceased, the solvents were pumped off in vacuo, and theresidue stripped from toluene. This was again taken up in CH₂Cl₂ (200mL), and excess dimethyl amine was bubbled into the mixture, which wasthen sealed off and stirred overnight at room temperature. The solventswere pumped off to give the crudeN,N,4-trimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide,which was used without further purification in the next step.

5-chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(0.102 g, 0.298 mmol),N,N,4-trimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamidefrom above, (0.129 g, 0.447 mmol), and K₂CO₃ (0.123 g, 0.894 mmol), weretaken up in dioxane (6 mL) and water (1.2 mL). The mixture was degassedwith argon for 30 min and tetrakis(triphenyl-phosphine)palladium(0)(0.026 g, 0.022 mmol) was added. The mixture was then heated under argonat 95° C. for 18 h. The solvents were pumped off, and after aqueousworkup, the crude material was flashed on silica gel (15 g), eluted witha EtOAc/CH₂Cl₂ gradient to give the title compound as a white amorphoussolid. mp 144-147° C. LC-MS m/z 470 (M+H)⁺, 2.02 min (ret time).

149b)3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N,4-trimethylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N,4-trimethylbenzamide(0.089 g, 0.19 mmol) was dissolved in CH₂Cl₂ (10 mL) and 50-60%3-chloroperoxybenzoic acid (0.118 g, 0.38 mmol) was added and themixture stirred overnight. The solvents were pumped off, and the residueflashed on silica gel eluted with CH₂Cl₂ −90% EtOAc/CH₂Cl₂ to give3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N,4-trimethylbenzamide.LC-MS m/z 502 (M+H)⁺, 1.78 min (ret time).

149c)3-[8-(2,6-difluorophenyl)-2-(4-methyl-1-piperazinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N,4-trimethylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N,4-trimethylbenzamide(0.050 g, 0.1 mmol) was dissolved in THF (5 mL) and 1-methylpiperazine(0.050 g, 0.5 mmol) was added. The reaction was stirred under argonovernight. The solvents were pumped off in vacuo. The residue was flashchromatographed on silica gel (15 g) eluted with CH₂Cl₂ to 6:0.5:0.05,CH₂Cl₂:ethanol:NH₄OH to give the title compound as a white amorphoussolid. mp 159-162° C. LC-MS m/z 522 (M+H)⁺, 1.59 min (ret time).

Example 150N-4-biphenylyl-3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzamidetrifluoroacetate

Prepared following General Procedure for HATU Couplings. Reversed-phaseHPLC (10-90% gradient of acetonitrile in water with 0.1% TFA) providedthe title compound 4.4 mg (19%). LC-MS m/z 634 (M+H)⁺.

Example 1513-(8-(2,6-difluorophenyl)-2-{[3-(dimethylamino)propyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(phenylmethyl)benzamide

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide(0.056 g, 0.1 mmol) was dissolved in THF (5 mL) andN,N-dimethyl-1,3-propanediamine (0.035 g, 0.3 mmol) was added. Thereaction was carried out and worked up as in Example 148 to give thetitle compound as a white amorphous solid. mp 141-144° C. LC-MS m/z 586(M+H)⁺, 1.52 min (ret time).

Example 1523-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,N,4-trimethylbenzamide

The reaction was carried out and worked up as in Example 149c exceptsubstituting dimethylaminoethylamine (0.044 g, 0.5 mmol) for1-methylpiperazine to give the title compound as a white amorphoussolid. mp 138-142° C. LC-MS m/z 510 (M+H)⁺, 1.31 min (ret time).

Example 1533-[8-(2,6-difluorophenyl)-2-({2-[1-methylethyl)amino]ethyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N,4-trimethylbenzamide

The reaction was carried out and worked up as in Example 149c exceptsubstituting (2-aminoethyl)(1-methylethyl)amine (0.051 g, 0.5 mmol) for1-methylpiperazine to give the title compound as a white amorphoussolid. mp 130-133° C. LC-MS m/z 524 (M+H)⁺, 1.36 min (ret time).

Example 1543-{8-(2,6-difluorophenyl)-2-[[-3-(dimethylamino)propyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N,N,4-trimethylbenzamide

The reaction was carried out and worked up as in Example 149c exceptsubstituting [3-(dimethylamino)propyl]methylamine (0.058 g, 0.5 mmol)for 1-methylpiperazine to give the title compound as a white amorphoussolid. mp 114-118° C. LC-MS m/z 538 (M+H)⁺, 1.49 min (ret time).

Example 1553-{8-(2,6-difluorophenyl)-2-[(1-methyl-4-piperidinyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N,N,4-trimethylbenzamide

The reaction was carried out and worked up as in Example 149c exceptsubstituting 1-methyl-4-piperidinamine (0.057 g, 0.5 mmol) for1-methylpiperazine to give the title compound as a white amorphoussolid. mp 163-165° C. LC-MS m/z 536 (M+H)⁺, 1.25 min (ret time).

Example 1563-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,N-diethyl-4-methylbenzamide156a)3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N-diethyl-4-methylbenzamide

The reaction was carried out and worked up as in example 149a exceptadding excess diethylamine instead of dimethylamine to give the crudeN,N-diethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.This was chromatographed on silica gel (100 g) eluted with a methylenechloride ethyl acetate gradient to give cleanN,N-diethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.LC-MS m/z 470 (M+H)⁺, 2.40 min (ret time).

5-chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(0.720 g, 2.1 mmol),N,N-diethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamidefrom above (1.09 g, 3.15 mmol), and K₂CO₃ (0.868 g, 6.3 mmol), weretaken up in dioxane (42 mL) and water (8.5 mL). The mixture was degassedwith argon for 30 min and tetrakis-(triphenylphosphine)palladium(0)(0.183 g, 0.15 mmol) was added. The mixture was then heated under argonat 95° C. for 18 h. The solvents were pumped off and after aqueousworkup, the crude material was flashed on silica gel (150 g) eluted witha EtOAc/CH₂Cl₂ gradient to give the title compound as a white amorphoussolid. mp 127-129° C. LC-MS m/z 498 (M+H)⁺, 2.11 min (ret time).

156b)3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N-diethyl-4-methylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N-diethyl-4-methylbenzamide(0.63 g, 1.26 mmol) was dissolved in CH₂Cl₂ (100 mL) and 50-60%3-chloroperoxybenzoic acid (0.786 g, 2.52 mmol) was added and themixture stirred overnight. The solvents were pumped off, and the residueflashed on silica gel eluted with CH₂Cl₂ −90% EtOAc/CH₂Cl₂ to give thetitle compound as a white amorphous solid. mp 132-135° C. LC-MS m/z 530(M+H)⁺, 1.81 min (ret time).

156c)3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,N-diethyl-4-methylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N-diethyl-4-methylbenzamide(0.053 g, 0.1 mmol) was dissolved in THF (5 mL) anddimethylaminoethylamine (0.044 g, 0.5 mmol) was added. The reaction wasstirred under argon overnight. The solvents were pumped off in vacuo,and the residue was flash chromatographed on silica gel (15 g) elutedwith CH₂Cl₂ to 6:0.5:0.05, CH₂Cl₂:ethanol:NH₄OH to give the titlecompound as a white amorphous solid. mp 125-127° C. LC-MS m/z 538(M+H)⁺, 1.57 min (ret time).

Example 1573-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-[4-(ethyloxy)phenyl]-4-methylbenzamidetrifluoroacetate

Prepared following General Procedure for HATU Couplings. Reversed-phaseHPLC (10-90% gradient of acetonitrile in water with 0.1% TFA) providedthe title compound 5.1 mg (24%). LC-MS m/z 602 (M+H)⁺.

Example 1583-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino{-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-[4-(methyloxy)phenyl]benzamidetrifluoroacetate

Prepared following General Procedure for HATU Couplings. Reversed-phaseHPLC (10-90% gradient of acetonitrile in water with 0.1% TFA) providedthe title compound 3.4 mg (16%). LC-MS m/z 588 (M+H)⁺.

Example 1593-{8-(2,6-difluorophenyl)-2-[(1-methyl-4-piperidinyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N,N-diethyl-4-methylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N-diethyl-4-methylbenzamide(0.053 g, 0.1 mmol) was dissolved in THF (5 mL) and1-methyl-4-piperidinamine (0.044 g, 0.5 mmol) was added. The reactionwas stirred under argon overnight. The solvents were pumped off invacuo, and the residue was purified by mass directed auto prep. Thefractions were evaporated, and aqueous basic workup gave the titlecompound as a white amorphous solid. mp 165-169° C. LC-MS m/z 564(M+H)⁺, 1.44 min (ret time).

Example 1603-{8-(2,6-difluorophenyl)-2-({2-[(1-methylethyl)amino]ethyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N-diethyl-4-methylbenzamide

The reaction was carried out and worked up as in Example 156c exceptsubstituting (2-aminoethyl)(1-methylethyl)amine (0.051 g, 0.5 mmol) fordimethylaminoethylamine to give the title compound as a white amorphoussolid. mp 89-91° C. LC-MS m/z 552 (M+H)⁺, 1.32 min (ret time).

Example 1613-{8-(2,6-difluorophenyl)-2-[[3-(dimethylamino)propyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N,N-diethyl-4-methylbenzamide

The reaction was carried out and worked up as in Example 156c exceptsubstituting [3-(dimethylamino)propyl]methylamine (0.058 g, 0.5 mmol)for dimethylaminoethyl-amine to give the title compound as a whiteamorphous solid. mp 106-108° C. LC-MS m/z 566 (M+H)⁺, 1.69 min (rettime).

Example 1623-[8-(2,6-difluorophenyl)-2-(4-methyl-1-piperazinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,N-diethyl-4-methylbenzamide

The reaction was carried out and worked up as in Example 156c exceptsubstituting 1-methylpiperazine (0.05 g, 0.5 mmol) fordimethylaminoethylamine to give the title compound as a white amorphoussolid. mp (dec) 201-205° C. LC-MS m/z 550 (M+H)⁺, 1.35 min (ret time).

Example 1633-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,4-dimethylbenzamide163a)3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoicacid (0.59 g, 1.33 mmol) was taken up in CH₂Cl₂ (75 mL), anddiisopropylethylamine (0.7 mL, 4 mmol) was added followed by HATU (0.556g, 1.46 mmol). Gaseous methyl amine was then bubbled in very slowlyuntil reaction was complete. Aqueous workup followed by chromatographyon silica gel (100 g) eluted with CH₂Cl₂ −90% EtOAc/CH₂Cl₂ gave thetitle compound as a white amorphous solid. mp 273-275° C. LC-MS m/z 456(M+H)⁺, 1.85 min (ret time).

163b)3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide,(0.592 g, 1.3 mmol) was taken up in CH₂Cl₂ (75 mL), and 50-60%3-chloroperoxybenzoic acid (0.84 g, 2.7 mmol) was added. The mixture wasstirred overnight under argon. The solvent was pumped off in vacuo, andthe residue was chromatographed on silica gel (80 g) eluted with 0-10%MeOH/CH₂Cl₂. Crystallization from MeOH gave the title compound as awhite crystalline solid. mp 275-278° C. LC-MS m/z 488 (M+H)⁺, 1.58 min(ret time).

163c)3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,4-dimethylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide(0.03 g, 0.06 mmol) was dissolved in THF (5 mL) anddimethylaminoethylamine (0.026 g, 0.3 mmol) was added. The reaction wasstirred under argon overnight. The solvents were pumped off in vacuo,and the residue was flash chromatographed on silica gel (15 g) elutedwith CH₂Cl₂ to 6:0.5:0.05, CH₂Cl₂:ethanol:NH₄OH to give the titlecompound as a white amorphous solid. mp (dec) 155-158° C. LC-MS m/z 496(M+H)⁺, 1.29 min (ret time).

Example 1643-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(3-methylphenyl)benzamidetrifluoroacetate

Prepared following General Procedure for HATU Couplings. Reversed-phaseHPLC (10-90% gradient of acetonitrile in water with 0.1% TFA) providedthe title compound 4.5 mg (21%). LC-MS m/z 583 (M+H)⁺.

Example 165N-(2,4-difluorophenyl)-3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound 5 mg (23%). LC-MS m/z 594 (M +H)⁺.

Example 1663-(8-(2,6-difluorophenyl)-2-{[3-(dimethylamino)propyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,4-dimethylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide(0.032 g, 0.031 mmol) was dissolved in THF (5 mL) andN,N-dimethyl-1,3-propanediamine (0.032 g, 0.31 mmol) was added. Thereaction was stirred under argon overnight. The solvents were pumped offin vacuo, and the residue was flash chromatographed on silica gel (15 g)eluted with CH₂Cl₂ to 6:0.5:0.05, CH₂Cl₂:ethanol:NH₄OH to give the titlecompound as a white amorphous solid. mp (dec) 164-167° C. LC-MS m/z 510(M+H)⁺, 1.31 min (ret time).

Example 1673-[8-(2,6-difluorophenyl)-2-({2-[(1-methylethyl)amino]ethyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide(0.031 g, 0.064 mmol) was dissolved in THF (5 mL) and(2-aminoethyl)(1-methylethyl)amine (0.032 g, 0.31 mmol) was added. Thereaction was stirred under argon for ten days. The solvents were pumpedoff in vacuo, and the residue was flash chromatographed on silica gel(15 g) eluted with CH₂Cl₂ to 6:0.5:0.05, CH₂Cl₂:ethanol:NH₄OH to givethe title compound as a white amorphous solid. mp (dec) 136-139° C.LC-MS m/z 510 (M+H)⁺, 1.35 min (ret time).

Example 1683-[8-(2,6-difluorophenyl)-2-({3-[(1-methylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide(0.036 g, 0.074 mmol) was dissolved in THF (5 mL) and(3-aminopropyl)(1-methylethyl)amine (0.045 g, 0.37 mmol) was added. Thereaction was stirred under argon overnight. The solvents were pumped offin vacuo, and the residue was flash chromatographed on silica gel (15 g)eluted with CH₂Cl₂ to 6:0.5:0.05, CH₂Cl₂:ethanol:NH₄OH to give the titlecompound as a white amorphous solid. mp (dec) 153-157° C. LC-MS m/z524.6 (M+H)⁺, 1.31 min (ret time).

Example 1693-[8-(2,6-difluorophenyl)-2-(4-methyl-1-piperazinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide(0.033 g, 0.0678 mmol) was dissolved in THF (5 mL) and1-methylpiperazine (0.034 g, 0.34 mmol) was added. The reaction washeated to 45° C. for 4 h and then cooled to room temperature overnight.The solvents were pumped off in vacuo, and the residue was flashchromatographed on silica gel (15 g) eluted with CH₂Cl₂ to 6:0.5:0.05,CH₂Cl₂:ethanol:NH₄OH to give the title compound as a white amorphoussolid. mp (dec) 164-168° C. LC-MS m/z 508 (M+H)⁺, 1.34 min (ret time).

Example 1703-8-(2,6-difluorophenyl)-2-({3-[(1,1-dimethylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide(0.036 g, 0.074 mmol) was dissolved in THF (5 mL) and(3-aminopropyl)(1,1-dimethylethyl)amine (0.045 g, 0.37 mmol) was added.The reaction was stirred under argon for 2 days. The solvents werepumped off in vacuo, and the residue was flash chromatographed on silicagel (15 g) eluted with CH₂Cl₂ to 6:0.5:0.05, CH₂Cl₂:ethanol:NH₄OH togive the title compound as a white amorphous solid. mp (dec) 166-170° C.LC-MS m/z 538 (M+H)⁺, 1.38 min (ret time).

Example 1713-[2-{[3-(dibutylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide(0.03 g, 0.062 mmol) was dissolved in THF (5 mL) and(3-aminopropyl)dibutylamine (0.058 g, 0.31 mmol) was added. The reactionwas stirred under argon for 24 h. The solvents were pumped off in vacuo,and the residue was flash chromatographed on silica gel (15 g) elutedwith CH₂Cl₂ to 6:0.5:0.05, CH₂Cl₂:ethanol:NH₄OH to give the titlecompound as a white amorphous solid. mp 112-115° C. LC-MS m/z 594.6(M+H)⁺, 1.59 min (ret time).

Example 1723-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide(0.03 g, 0.062 mmol) was dissolved in THF (5 mL) and(3-aminopropyl)diethylamine (0.041 g, 0.31 mmol) was added. The reactionwas stirred under argon for 24 h. The solvents were pumped off in vacuo,and the residue was flash chromatographed on silica gel (15 g) elutedwith CH₂Cl₂ to 6:0.5:0.05, CH₂Cl₂:ethanol:NH₄OH to give the titlecompound as a white amorphous solid. mp 133-136° C. LC-MS m/z 538(M+H)⁺, 1.34 min (ret time).

Example 1733-{8-(2,6-difluorophenyl)-2-[(1-methyl-4-piperidinyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N,4-dimethylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide,(0.02 g, 0.041 mmol) was dissolved in THF (5 mL) and1-methyl-4-piperidinamine (0.024 g, 0.21 mmol) was added. The reactionmixture was stirred at room temperature for 24 hours, but the reactionhad not gone to completion. The reaction was heated to 45° C. for 24 hand then cooled to room temperature. The solvents were pumped off invacuo, and the residue was flash chromatographed on silica gel (10 g)eluted with CH₂Cl₂ to 6:0.5:0.05, CH₂Cl₂:ethanol:NH₄OH to give the titlecompound as a white amorphous solid. mp (dec) 205-209° C. LC-MS m/z 522(M+H)⁺, 1.29 min (ret time).

Example 1743-{8-(2,6-difluorophenyl)-2-[[3-(dimethylamino)propyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N,4-dimethylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide,(0.02 g, 0.041 mmol) was dissolved in THF (5 mL) and[3-(dimethylamino)propyl]methylamine (0.024 g, 0.205 mmol) was added.The reaction mixture was stirred at room temperature for 6 days, but thereaction had not gone to completion. The reaction was heated to 45° C.overnight and then cooled to room temperature. The solvents were pumpedoff in vacuo, and the residue was flash chromatographed on silica gel(10 g) eluted with CH₂Cl₂ to 6:0.5:0.05, CH₂Cl₂:ethanol:NH₄OH to givethe title compound as a white amorphous solid. mp 163-165° C. LC-MS m/z524.6 (M+H)⁺, 1.47 min (ret time).

Example 1753-{8-(2,6-difluorophenyl)-7-oxo-2-[4-(1-pyrrolidinyl)-1-piperidinyl]-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N,4-dimethylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide(0.015 g, 0.031 mmol) was dissolved in THF (5 mL) and4-(1-pyrrolidinyl)piperidine (0.024 g, 0.155 mmol) was added. Thereaction mixture was stirred at room temperature for 4 days. Thesolvents were pumped off in vacuo, and the residue was flashchromatographed on silica gel (10 g) eluted with CH₂Cl₂ to 6:0.5:0.05,CH₂Cl₂:ethanol:NH₄OH to give the title compound as a white amorphoussolid. mp (dec) 189-194° C. LC-MS m/z 562 (M+H)⁺, 1.62 min (ret time).

Example 1763-[2-(1,4′-bipiperidin-1′-yl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide(0.015 g, 0.031 mmol) was dissolved in THF (5 mL) and 1,4′-bipiperidine(0.026 g, 0.155 mmol) was added. The reaction mixture was stirred atroom temperature for 4 days. The solvents were pumped off in vacuo, andthe residue was flash chromatographed on silica gel (10 g) eluted withCH₂Cl₂ to 6:0.5:0.05, CH₂Cl₂:ethanol:NH₄OH to give the title compound asa white amorphous solid. mp (dec) 179-184° C. LC-MS m/z 576 (M+H)⁺, 1.54min (ret time).

Example 1773-[8-(2,6-difluorophenyl)-2-({3-[methyl(phenyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound 5 mg (19%). LC-MS m/z 600 (M+H)⁺.

Example 1783-(8-(2,6-difluorophenyl)-2-{[2-(methyloxy)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 6.2 mg (28%). LC-MS m/z 511 (M+H)⁺.

Example 1793-[8-(2,6-difluorophenyl)-2-(4-methylhexahydro-1H-1,4-diazepin-1-yl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 8.5 mg (35%). LC-MS m/z 550 (M+H)⁺.

Example 1803-[8-(2,6-difluorophenyl)-2-(4-ethyl-1-piperazinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 8.5 mg (35%). LC-MS m/z 550 (M+H)⁺.

Example 1813-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(2-fluorophenyl)-4-methylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound 4.6 mg (22%). LC-MS m/z 576 (M+H)⁺.

Example 1823-(8-(2,6-difluorophenyl)-2-{[3-(hexahydro-1H-azepin-1-yl)propyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 12 mg (46%). LC-MS m/z 592 (M+H)⁺.

Example 1833-(8-(2,6-difluorophenyl)-7-oxo-2-{[3-(1-pyrrolidinyl)propyl]amino}-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 11 mg (44%). LC-MS m/z 564 (M+H)⁺.

Example 1843-(8-(2,6-difluorophenyl)-7-oxo-2-{[(3S)-1-(phenylmethyl)-3-pyrrolidinyl]amino}-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 11.4 mg (42%). LC-MS m/z 612 (M+H)⁺.

Example 1853-[8-(2,6-difluorophenyl)-2-({[(2S)-1-ethyl-2-pyrrolidinyl]methyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 9.1 mg (37%). LC-MS m/z 564 (M+H)⁺.

Example 1863-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)-1-methylethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 11.1 mg (47%). LC-MS m/z 538 (M+H)⁺.

Example 1873-(8-(2,6-difluorophenyl)-2-{[2-(1-methyl-2-pyrrolidinyl)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound 12.2 mg (49%). LC-MS m/z 564 (M+H)⁺.

Example 188

3-(8-(2,6-difluorophenyl)-7-oxo-2-{[2-(1-piperidinyl)ethyl]amino}-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 13.8 mg (56%). LC-MS m/z 564 (M+H)⁺.

Example 1893-(8-(2,6-difluorophenyl)-2-{[3-(1H-imidazol-1-yl)propyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 12.3 mg (50%). LC-MS m/z 561 (M+H)⁺.

Example 1903-(8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound 3.4 mg (15%). LC-MS m/z 527 (M+H)⁺.

Example 1913-[2-({2-[bis(1-methylethyl)amino]ethyl}amino)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 6.5 mg (25%). LC-MS m/z 580 (M+H)⁺.

Example 1923-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(5-methyl-1,3-thiazol-2-yl)benzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500mg) by elution with chloroform followedby ethyl acetate, 20% methanol/ethyl acetate and finally methanolprovided the title compound, 4.1 mg (20%). LC-MS m/z 579 (M+H)⁺.

Example 1933-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-4-pyridinylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound. 2.6 mg (13%). LC-MS m/z 559(M+H)⁺.

Example 194

3-(8-(2,6-difluorophenyl)-7-oxo-2-{[2-(phenylamino)ethyl]amino}-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 14 mg (56%). LC-MS m/z 572 (M+H)⁺.

Example 1953-(8-(2,6-difluorophenyl)-7-oxo-2-{[1-phenyl-2-(1-pyrrolidinyl)ethyl]amino}-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 9.2 mg (33%). LC-MS m/z 626 (M+H)⁺.

Example 1963-(8-(2,6-difluorophenyl)-7-oxo-2-{[2-phenyl-2-(1-pyrrolidinyl)ethyl]amino}-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 6.1 mg (22%). LC-MS m/z 626 (M+H)⁺.

Example 1973-[8-(2,6-difluorophenyl)-7-oxo-2-({2-[4-(phenylmethyl)-1-piperazinyl]ethyl}amino)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 12.5 mg (43%). LC-MS m/z 655 (M+H)⁺.

Example 1983-[8-(2,6-difluorophenyl)-7-oxo-2-(4-propyl-1-piperazinyl)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 3.4 mg (14%). LC-MS m/z 564 (M+H)⁺.

Example 1993-[2-(4-butyl-1-piperazinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 9 mg (35%). LC-MS m/z 578 (M+H)⁺.

Example 2003-(8-(2,6-difluorophenyl)-7-oxo-2-{[1-(phenylmethyl)-4-piperidinyl]amino}-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamide

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC without TFA provided the title compound 6.7 mg(24%). LC-MS m/z 626 (M+H)⁺.

Example 2013-[8-(2,6-difluorophenyl)-7-oxo-2-(2-propen-1-ylamino)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC without TFA provided the title compound, 3 mg (14%).LC-MS m/z 493 (M+H)⁺.

Example 2023-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-3-isoquinolinyl-4-methylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500mg) by elution with chloroform followedby ethyl acetate, 20% methanol/ethyl acetate and finally methanolprovided the title compound, 4.7 mg (21%). LC-MS m/z 609 (M+H)⁺.

Example 2033-[8-(2,6-difluorophenyl)-2-({2-ethyl(3-methylphenyl)amino]ethyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 9.8 mg (36%). LC-MS m/z 614 (M+H)⁺.

Example 204

3-[2-[[2-(diethylamino)ethyl](methyl)amino]-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamidetrifluoroacetate

Prepared following General Procedure for sulfoxide displacement.Reversed-phase HPLC (10-90% gradient of acetonitrile in water with 0.1%TFA) provided the title compound, 5.5 mg (22%). LC-MS m/z 566 (M+H)⁺.

Example 205N-(4-cyanophenyl)-3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound 2.4 mg (11%). LC-MS m/z 583 (M+H)⁺.

Example 2063-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-[3-(methylthio)phenyl]benzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 3.6 mg (17%). LC-MS m/z 604(M+H)⁺.

Example 2073-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-[4-(phenylcarbonyl)phenyl]benzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound 3.2 mg (13%). LC-MS m/z 662 (M+H)⁺.

Example 208 Butyl4-({[3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylphenyl]carbonyl}amino)benzoate

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 4 mg (17%). LC-MS m/z 658 (M+H)⁺.

Example 2093-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-[4-(1-piperidinylsulfonyl)phenyl]benzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 2.3 mg (9%). LC-MS m/z 704 (M+H)⁺.

Example 2103-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-[4-(phenyloxy)phenyl]benzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 3.2 mg (14%). LC-MS m/z 650(M+H)⁺.

Example 211N-[3-(aminocarbonyl)phenyl]-3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 5.5 mg (25%). LC-MS m/z 601(M+H)⁺.

Example 2123-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-methylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 8 mg (36%). LC-MS m/z 616 (M+H)⁺.

Example 2133-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(2-methylphenyl)benzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 7.1 mg (35%). LC-MS m/z 571(M+H)⁺.

Example 214N-(3-cyanophenyl)-3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 5.4 mg (26%). LC-MS m/z 583(M+H)⁺.

Example 215N-(3,5-difluorophenyl)-3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 3.6 mg (17%). LC-MS m/z 594(M+H)⁺.

Example 216N-(3-chlorophenyl)-3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 5 mg (23%). LC-MS m/z 592 (M+H)⁺.

Example 217N-(3-chloro-4-fluorophenyl)-3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 6.8 mg (31%). LC-MS m/z 610(M+H)⁺.

Example 218N-(4-chlorophenol)-3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 6.8 mg (32%). LC-MS m/z 592(M+H)⁺.

Example 2193-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-[4-(dimethylamino)phenyl]-4-methylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 9 mg (42%). LC-MS m/z 601 (M+H)⁺.

Example 2203-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-[4-(trifluoromethyl)phenyl]benzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 5.8 mg (26%). LC-MS m/z 626(M+H)⁺.

Example 221N-(4-acetylphenyl)-3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 4.4 mg (20%). LC-MS m/z 600(M+H)⁺.

Example 2223-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-[3-(phenyloxy)phenyl]benzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 5.7 mg (24%). LC-MS m/z 650(M+H)⁺.

Example 2233-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-1H-indazol-6-yl-4-methylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 9.3 mg (43%). LC-MS m/z 598(M+H)⁺.

Example 2243-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(2-methyl-1,3-benzothiazol-5-yl)benzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 5.3 mg (23%). LC-MS m/z 629(M+H)⁺.

Example 2253-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4′-fluoro-3-biphenylyl)-4-methylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 4 mg (17%). LC-MS m/z 652 (M+H)⁺.

Example 226N-[3-(aminosulfonyl)phenyl]-3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)-ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzamide

Prepared following General Procedure for HATU Couplings. Solid phaseextraction (SPE, aminopropyl, 500 mg) by elution with chloroformfollowed by ethyl acetate, 20% methanol/ethyl acetate and finallymethanol provided the title compound, 5.5 mg (24%). LC-MS m/z 637(M+H)⁺.

Example 2273-[2-[(3-aminopropyl)amino]-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide227a)3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide

To a stirring suspension of Oxone (817.96 g, 1.33 mole, 3 eq) in water(2142 mL, 10 vol) was added3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(214.21 g 0.443 mole, 1 eq) suspended in acetonitrile (4284 mL). Theresulting mixture was stirred at ambient temperature overnight. Themixture was then filtered and the residue stirred sequentially with 5%sodium metabisulfite (2×3000 mL) and water (1×300 mL). The filtrate fromthe reaction mixture was then diluted with water (2142 mL, 10 vol). Thesolid that formed was then collected by filtration. The solid was washedwell with water then dried at the pump to yield the title compound.LC-MS m/z 516 (M+H)+, 2.77 min (ret time). It was used without furtherpurification although corresponding sulfoxide was present (about 10%).

227b)3-[2-[(3-aminopropyl)amino]-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide

To3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(497 mg, 1.0 mmol) in dichloromethane (20 mL) was added1,3-propyldiamine (0.251 mL, 3.0 mL). The mixture was stirred overnight. The mixture was concentrated and separated by flashchromatography to afford the title compound (395 mg, 78%). LC-MS m/z 510(M+H)⁺.

227c)3-[2-[(3-aminopropyl)amino]-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamidetrifluoroacetate

To3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(497 mg, 1.0 mmol) in dichloromethane (20 mL) was added1,3-propyldiamine (0.251 mL, 3.0 mL). The mixture was stirred overnight. The mixture was concentrated and initial separation was carriedout with flash chromatography affording the title compound as a freebase (395 mg, 78%). Additional purification with a Gilson HPLC (with0.1% TFA) then afforded the title compound (129.9 mg). LC-MS m/z 510(M+H)⁺; ¹H-NMR (MeOD) δ 0.96 (t, J=7.40 Hz, 3H), 1.56-1.66 (m, 3H), 1.72(br. s, 2H), 2.31 (s, 3H), 2.77 (br. s, 2H), 3.22 (br. s, 2H), 3.33 (t,J=7.15 Hz, 2H), 4.12 (br. s, 2H), 7.16 (t, J=8.41 Hz, 2H), 7.44-7.59 (m,2H), 7.73 (s, 1H), 7.87 (d, J=8.03 Hz, 1H).

Example 2283-[2-{[3-(diethylamino)propyl]amino{-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoicacid 228a)5-chloro-7-{[3-(diethylamino)propyl]amino}-1-(2,6-difluorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-onetrifluoroacetate

To5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(275 mg, 0.767 mmol) in dichloromethane (15 mL) was addedN,N-diethyl-1,3-propyldiamine (0.181 mL, 1.15 mmol) and triethylamine(0.215 mL, 1.53 mmol). The mixture was stirred over night. The mixturewas concentrated and separated by Gilson HPLC (with 0.1% TFA) to affordthe title compound (207 mg, 64%).

228b)3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoicacid

To5-chloro-7-{[3-(diethylamino)propyl]amino}-1-(2,6-difluorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(207 mg, 0.488 mmol) in 1,4-dioxane (7.5 mL) and water (2.5 mL) wasadded 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid (0.192 g, 0.733 mmol), tetrakis(triphenylphosphine)-palladium(0)(28.3 mg, 0.024 mmol), and potassium carbonate (270 mg, 1.95 mmol). Themixture was heated with microwave for 15 min at 150° C., and thenallowed to cool to room temperature. The mixture was concentrated andseparated by HPLC to afford the title compound (66 mg, 26%). LC-MS m/z525 (M+H)⁺.

Example 229N-(8-(2,6-difluorophenyl)-4-{2-methyl-5-[(propylamino)carbonyl]phenyl}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)-β-alanine

To3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(100 mg, 0.2 mmol) in DMF (1 mL) was added β-alanine (35.6 mg, 0.4 mmol)and triethylamine (56.2 uL, 0.4 mmol). The mixture was heated withmicrowave at 100° C. for 2 hrs. The mixture was separated by HPLC toafford the title compound (45 mg, 43%). LC-MS m/z 525 (M+H)⁺.

Example 2303-(8-(2,6-difluorophenyl)-2-{[3-(ethylamino)propyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-propylbenzamideand the Corresponding Trifluoroacetate Salt 230a)3-[2-[(3-chloropropyl)amino]-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide

To3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(206 mg, 0.4 mmol) in DMF (4 mL) was added (3-chloropropyl)aminehydrochloride (78 mg, 0.6 mmol) and triethylamine (112 uL, 0.8 mmol).The mixture was heated with microwave at 60° C. for 2 hrs. The mixturewas separated by flash chromatography to afford the title compound (100mg, 47%).

230b)3-(8-(2,6-difluorophenyl)-2-{[3-(ethylamino)propyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-propylbenzamidetrifluoroacetate

To3-[2-[(3-chloropropyl)amino]-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(100 mg, 0.189 mmol) in DMF (2 mL) was added ethylamine (0.189 mL, 2.0 Min THF, 0.378 mmol) and potassium carbonate (0.104 g, 0.756 mmol). Themixture was heated with microwave irradiations at 100° C. for about 30min. The mixture was concentrated and separated by Gilson HPLC (with0.1% TFA) affording the title compound (11 mg, 11%). LC-MS m/z 538(M+H)⁺; ¹H-NMR (MeOD) δ 1.02 (t, J=7.30 Hz, 3H), 1.08 (t, J=6.92 Hz,3H), 1.63-1.74 (m, 2H), 1.98-2.07 (m, 2H), 2.34 (s, 3H), 3.10-3.19 (m,2H), 3.39 (t, J=6.80 Hz, 4H), 3.43-3.52 (m, 1H), 3.53-3.64 (m, 1H), 3.78(d, J=15.86 Hz, 1H), 4.19 (d, J=16.11 Hz, 1H), 7.13 (t, J=8.31 Hz, 2H),7.34-7.48 (m, 1H), 7.63 (d, J=7.81 Hz, 1H), 7.79 (s, 1H), 7.99 (d,J=8.06 Hz, 1H).

230c)3-(8-(2,6-difluorophenyl)-2-{[3-(ethylamino)propyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-propylbenzamide

To3-[2-[(3-chloropropyl)amino]-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide(265 mg, 0.50 mmol) in DMF (10 mL) was added ethylamine (1.25 mL, 2.0 Min THF, 2.5 mmol) and potassium carbonate (0.276 g, 2.0 mmol). Themixture was heated at 50° C. for about 20 hours, then at 80° C. forabout 4 hours. The mixture was diluted with EtOAc (50 mL), washed withH2O (30 mL+15 mL×2) and brine (20 mL). The organic layers were collectedand concentrated. Flash chromatograph afforded the title compound (134mg, 50%). LC-MS m/z 538 (M+H)⁺; ¹H-NMR (MeOD) δ 0.96-1.02 (m, 6H),1.61-1.72 (m, 2H), 1.85-1.96 (m, 2H), 2.30 (s, 3H), 3.07 (q, J=7.11 Hz,2H), 3.19-3.29 (m, 3H), 3.33-3.40 (m, 3H), 3.83 (d, 1H), 3.90 (d, 1H),6.83-6.99 (m, 3H), 7.51 (d, J=8.03 Hz, 1H), 7.69 (d, J=1.76 Hz, 1H),7.87 (dd, J=7.91, 1.88 Hz, 1H).

Methods of Treatment

The compounds of (I) and (Ia), (II) and (IIa), (III) and (IIIa), (IV)and (IVa), (V) and (Va), (VI), (VIa-VIi), (VIII) and (VIIIa), (IX) and(IXa), (A), (A1), (B), and (B1), or a pharmaceutically acceptable salt,solvate, or physiologically functional derivative thereof can be used inthe manufacture of a medicament for the prophylactic or therapeutictreatment of any disease state in a human, or other mammal, which isexacerbated or caused by excessive or unregulated cytokine production bysuch mammal's cell, such as but not limited to monocytes and/ormacrophages.

For purposes herein, compounds of Formula (I) and (Ia), (II) and (IIa),(III) and (IIIa), (IV) and (IVa), (V) and (Va), (VI), (VIa-VIi), (VIII)and (VIIIa), (IX) and (IXa), (A), (A1), (B), and (B1), etc. will all bereferred to as compounds of Formula (I) herein unless otherwiseindicated.

Compounds of Formula (I) are capable of inhibiting proinflammatorycytokines, such as IL-1, IL-6, IL-8, and TNF and are therefore of use intherapy. IL-1, IL-6, IL-8 and TNF affect a wide variety of cells andtissues and these cytokines, as well as other leukocyte-derivedcytokines, are important and critical inflammatory mediators of a widevariety of disease states and conditions. The inhibition of thesepro-inflammatory cytokines is of benefit in controlling, reducing andalleviating many of these disease states.

Accordingly, the present invention provides a method of treating acytokine-mediated disease which comprises administering an effectivecytokine-interfering amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

Compounds of Formula (I) are capable of inhibiting inducibleproinflammatory proteins, such as COX-2, also referred to by many othernames such as prostaglandin endoperoxide synthase-2 (PGHS-2) and aretherefore of use in therapy. These proinflammatory lipid mediators ofthe cyclooxygenase (CO) pathway are produced by the inducible COX-2enzyme. Regulation, therefore of COX-2 which is responsible for thethese products derived from arachidonic acid, such as prostaglandinsaffect a wide variety of cells and tissues are important and criticalinflammatory mediators of a wide variety of disease states andconditions. Expression of COX-1 is not effected by compounds of Formula(I). This selective inhibition of COX-2 may alleviate or spareulcerogenic liability associated with inhibition of COX-1 therebyinhibiting prostaglandins essential for cytoprotective effects. Thusinhibition of these pro-inflammatory mediators is of benefit incontrolling, reducing and alleviating many of these disease states. Mostnotably these inflammatory mediators, in particular prostaglandins, havebeen implicated in pain, such as in the sensitization of pain receptors,or edema. This aspect of pain management therefore includes treatment ofneuromuscular pain, headache, cancer pain, and arthritis pain. Compoundsof Formula (I) or a pharmaceutically acceptable salt thereof, are of usein the prophylaxis or therapy in a human, or other mammal, by inhibitionof the synthesis of the COX-2 enzyme.

Accordingly, the present invention provides a method of inhibiting thesynthesis of COX-2 which comprises administering an effective amount ofa compound of Formula (I) or a pharmaceutically acceptable salt thereof.The present invention also provides for a method of prophylaxistreatment in a human, or other mammal, by inhibition of the synthesis ofthe COX-2 enzyme.

In particular, compounds of Formula (I) or a pharmaceutically acceptablesalt thereof are of use in the prophylaxis or therapy of any diseasestate in a human, or other mammal, which is exacerbated by or caused byexcessive or unregulated IL-1, IL-6, IL-8 or TNF production by suchmammal's cell, such as, but not limited to, monocytes and/ormacrophages.

Accordingly, in another aspect, this invention relates to a method ofinhibiting the production of IL-1 in a mammal in need thereof whichcomprises administering to said mammal an effective amount of a compoundof Formula (I) or a pharmaceutically acceptable salt thereof.

There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease.These include rheumatoid arthritis, osteoarthritis, meningitis, ischemicand hemorrhagic stroke, neurotrauma/closed head injury, stroke,endotoxemia and/or toxic shock syndrome, other acute or chronicinflammatory disease states such as the inflammatory reaction induced byendotoxin or inflammatory bowel disease, tuberculosis, atherosclerosis,muscle degeneration, multiple sclerosis, cachexia, bone resorption,psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis,rubella arthritis and acute synovitis. Recent evidence also links IL-1activity to diabetes, pancreatic β cell diseases and Alzheimer'sdisease.

Use of a CSAID inhibitor compound for the treatment of CSBP mediateddisease states, can include, but not be limited to neurodegenerativediseases, such as Alzheimer's disease (as noted above), Parkinson'sdisease and multiple sclerosis, etc.

In a further aspect, this invention relates to a method of inhibitingthe production of TNF in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof.

Excessive or unregulated TNF production has been implicated in mediatingor exacerbating a number of diseases including rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions, sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, chronic pulmonary inflammatory disease and chronic obstructivepulmonary disease, silicosis, pulmonary sarcoisosis, bone resorptiondiseases, such as osteoporosis, cardiac, brain and renal reperfusioninjury, graft vs. host reaction, allograft rejections, fever andmyalgias due to infection, such as influenza, brain infections includingencephalitis (including HIV-induced forms), cerebral malaria,meningitis, ischemic and hemorrhagic stroke, cachexia secondary toinfection or malignancy, cachexia secondary to acquired immunedeficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloidformation, scar tissue formation, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis and pyresis.

Compounds of Formula (I) are also useful in the treatment of viralinfections, where such viruses are sensitive to upregulation by TNF orwill elicit TNF production in vivo. The viruses contemplated fortreatment herein are those that produce TNF as a result of infection, orthose which are sensitive to inhibition, such as by decreasedreplication, directly or indirectly, by the TNF inhibiting-compounds ofFormula (I). Such viruses include, but are not limited to HIV-1, HIV-2and HIV-3, Cytomegalovirus (CMV), Influenza, adenovirus and the Herpesgroup of viruses, such as but not limited to, Herpes Zoster and HerpesSimplex. Accordingly, in a further aspect, this invention relates to amethod of treating a mammal afflicted with a human immunodeficiencyvirus (HIV) which comprises administering to such mammal an effectiveTNF inhibiting amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

It is also recognized that both IL-6 and IL-8 are produced duringrhinovirus (HRV) infections and contribute to the pathogenesis of commoncold and exacerbation of asthma associated with HRV infection (Turner etal. (1998), Clin. Infec. Dis., Vol. 26, p 840; Teren et al. (1997), Am.J. Respir. Crit. Care Med., Vol. 155, p 1362; Grunberg et al. (1997),Am. J. Respir. Crit. Care Med. Vol. 156, p 609 and Zhu et al, J Clin.Invest (1996), 97:421). It has also been demonstrated in vitro thatinfection of pulmonary epithelial cells with HRV results in productionof IL-6 and IL-8 (Subauste et al., J. Clin. Invest. 1995, 96:549.)Epithelial cells represent the primary site of infection of HRV.Therefore another aspect of the present invention is a method oftreatment to reduce inflammation associated with a rhinovirus infection,not necessarily a direct effect on virus itself.

Compounds of Formula (I) may also be used in association with theveterinary treatment of mammals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are not limited to, lentivirus infectionssuch as, equine infectious anaemia virus, caprine arthritis virus, visnavirus, or maedi virus or retrovirus infections, such as but not limitedto feline immunodeficiency virus (FIV), bovine immunodeficiency virus,or canine immunodeficiency virus or other retroviral infections.

The compounds of Formula (I) may also be used topically in the treatmentor prophylaxis of topical disease states mediated by or exacerbated byexcessive cytokine production, such as by IL-1 or TNF respectively, suchas inflamed joints, eczema, psoriasis and other inflammatory skinconditions such as sunburn; inflammatory eye conditions includingconjunctivitis; pyresis, pain and other conditions associated withinflammation. Periodontal disease has also been implemented in cytokineproduction, both topically and systemically. Hence use of compounds ofFormula (I) to control the inflammation associated with cytokineproduction in such peroral diseases such as gingivitis and periodontitisis another aspect of the present invention.

Compounds of Formula (I) have also been shown to inhibit the productionof IL-8 (Interleukin-8, NAP). Accordingly, in a further aspect, thisinvention relates to a method of inhibiting the production of IL-8 in amammal in need thereof which comprises administering to said mammal aneffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

There are many disease states in which excessive or unregulated IL-8production is implicated in exacerbating and/or causing the disease.These diseases are characterized by massive neutrophil infiltration suchas, psoriasis, inflammatory bowel disease, asthma, cardiac, brain andrenal reperfusion injury, adult respiratory distress syndrome,thrombosis and glomerulonephritis. All of these diseases are associatedwith increased IL-8 production which is responsible for the chemotaxisof neutrophils into the inflammatory site. In contrast to otherinflammatory cytokines (IL-1, TNF, and IL-6), IL-8 has the uniqueproperty of promoting neutrophil chemotaxis and activation. Therefore,the inhibition of IL-8 production would lead to a direct reduction inthe neutrophil infiltration.

The compounds of Formula (I) are administered in an amount sufficient toinhibit cytokine, in particular IL-1, IL-6, IL-8 or TNF, production suchthat it is regulated down to normal levels, or in some case to subnormallevels, so as to ameliorate or prevent the disease state. Abnormallevels of IL-1, IL-6, IL-8 or TNF, for instance in the context of thepresent invention, constitute: (i) levels of free (not cell bound) IL-1,IL-6, IL-8 or TNF greater than or equal to 1 picogram per ml; (ii) anycell associated IL-1, IL-6, IL-8 or TNF; or (iii) the presence of IL-1,IL-6, IL-8 or TNF mRNA above basal levels in cells or tissues in whichIL-1, IL-6, IL-8 or TNF, respectively, is produced.

The discovery that the compounds of Formula (I) are inhibitors ofcytokines, specifically IL-1, IL-6, IL-8 and TNF is based upon theeffects of the compounds of Formulas (I) on the production of the IL-1,IL-8 and TNF in in vitro assays which are described herein.

As used herein, the term “inhibiting the production of IL-1 (IL-6, IL-8or TNF)” refers to:

a) a decrease of excessive in vivo levels of the cytokine (IL-1, IL-6,IL-8 or TNF) in a human to normal or sub-normal levels by inhibition ofthe in release of the cytokine by all cells, including but not limitedto monocytes or macrophages;

b) a down regulation, at the genomic level, of excessive in vivo levelsof the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal orsub-normal levels;

c) a down regulation, by inhibition of the direct synthesis of thecytokine (IL-1, IL-6, IL-8 or TNF) as a postranslational event; or

d) a down regulation, at the translational level, of excessive in vivolevels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal orsub-normal levels.

As used herein, the term “TNF mediated disease or disease state” refersto any and all disease states in which TNF plays a role, either byproduction of TNF itself, or by TNF causing another monokine to bereleased, such as but not limited to IL-1, IL-6 or IL-8. A disease statein which, for instance, IL-1 is a major component, and whose productionor action, is exacerbated or secreted in response to TNF, wouldtherefore be considered a disease stated mediated by TNF.

As used herein, the term “cytokine” refers to any secreted polypeptidethat affects the functions of cells and is a molecule which modulatesinteractions between cells in the immune, inflammatory or hematopoieticresponse. A cytokine includes, but is not limited to, monokines andlymphokines, regardless of which cells produce them. For instance, amonokine is generally referred to as being produced and secreted by amononuclear cell, such as a macrophage and/or monocyte. Many other cellshowever also produce monokines, such as natural killer cells,fibroblasts, basophils, neutrophils, endothelial cells, brainastrocytes, bone marrow stromal cells, epideral keratinocytes andB-lymphocytes. Lymphokines are generally referred to as being producedby lymphocyte cells. Examples of cytokines include, but are not limitedto, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8),Tumor Necrosis Factor-alpha (TNF-α) and Tumor Necrosis Factor beta(TNF-β).

As used herein, the term “cytokine interfering” or “cytokine suppressiveamount” refers to an effective amount of a compound of Formula (I) whichwill cause a decrease in the in vivo levels of the cytokine to normal orsub-normal levels, when given to a patient for the prophylaxis ortreatment of a disease state which is exacerbated by, or caused by,excessive or unregulated cytokine production.

As used herein, the cytokine referred to in the phrase “inhibition of acytokine, for use in the treatment of a HIV-infected human” is acytokine which is implicated in (a) the initiation and/or maintenance ofT cell activation and/or activated T cell-mediated HIV gene expressionand/or replication and/or (b) any cytokine-mediated disease associatedproblem such as cachexia or muscle degeneration.

As TNF-β (also known as lymphotoxin) has close structural homology withTNF-α (also known as cachectin) and since each induces similar biologicresponses and binds to the same cellular receptor, both TNF-α and TNF-βare inhibited by the compounds of the present invention and thus areherein referred to collectively as “TNF” unless specifically delineatedotherwise.

A member of the MAP kinase family, alternatively termed CSBP, p38, orRK, has been identified independently by several laboratories.Activation of this novel protein kinase via dual phosphorylation hasbeen observed in different cell systems upon stimulation by a widespectrum of stimuli, such as physicochemical stress and treatment withlipopolysaccharide or proinflammatory cytokines such as interleukin-1and tumor necrosis factor. The cytokine biosynthesis inhibitors, of thepresent invention, compounds of Formula (I) have been determined to bepotent and selective inhibitors of CSBP/p38/RK kinase activity. It hasbeen found that some of the compounds of Formula I exhibit reversibletime-dependent inhibition of the p38 kinase due to the kinetics of slowbinding and/or slow dissociation, resulting in an improved apparent IC50when a compound has been preincubated with the enzyme or with cells.This slow, tight binding property may contribute to enhanced potency ofsuch compounds both in vitro and in vivo.

These inhibitors are of aid in determining the signaling pathwaysinvolvement in inflammatory responses. In particular, for the first timea definitive signal transduction pathway can be prescribed to the actionof lipopolysaccharide in cytokine production in macrophages. In additionto those diseases already noted, treatment of stroke, neurotrauma,cardiac and renal reperfusion injury, congestive heart failure, coronaryarterial bypass grafting (CABG) surgery, chronic renal failure,angiogenesis & related processes, such as cancer, thrombosis,glomerulonephritis, diabetes and pancreatic β cells, multiple sclerosis,muscle degeneration, eczema, psoriasis, sunburn, and conjunctivitis arealso included.

The CSBP inhibitors were subsequently tested in a number of animalmodels for anti-inflammatory activity. Model systems were chosen thatwere relatively insensitive to cyclooxygenase inhibitors in order toreveal the unique activities of cytokine suppressive agents. Theinhibitors exhibited significant activity in many such in vivo studies.Most notable are its effectiveness in the collagen-induced arthritismodel and inhibition of TNF production in the endotoxic shock model. Inthe latter study, the reduction in plasma level of TNF correlated withsurvival and protection from endotoxic shock related mortality. Also ofgreat importance is the compounds effectiveness in inhibiting boneresorption in a rat fetal long bone organ culture system. Griswold etal., (1988) Arthritis Rheum. 31:1406-1412; Badger, et al., (1989) Circ.Shock 27, 51-61; Votta et al., (1994) in vitro. Bone 15, 533-538; Lee etal., (1993). B Ann. N.Y. Acad. Sci. 696, 149-170.

Chronic diseases which have an inappropriate angiogenic component arevarious ocular neovasularizations, such as diabetic retinopathy andmacular degeneration. Other chronic diseases which have an excessive orincreased proliferation of vasculature are tumor growth and metastasis,atherosclerosis, and certain arthritic conditions. Therefore CSBP kinaseinhibitors will be of utility in the blocking of the angiogeniccomponent of these disease states.

The term “excessive or increased proliferation of vasculatureinappropriate angiogenesis” as used herein includes, but is not limitedto, diseases which are characterized by hemangiomas and ocular diseases.

The term “inappropriate angiogenesis” as used herein includes, but isnot limited to, diseases which are characterized by vesicleproliferation with accompanying tissue proliferation, such as occurs incancer, metastasis, arthritis and atherosclerosis.

Accordingly, the present invention provides a method of treating a CSBPkinase mediated disease in a mammal in need thereof, preferably a human,which comprises administering to said mammal, an effective amount of acompound of Formula (I) or a pharmaceutically acceptable salt thereof.

In order to use a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof in therapy, it will normally be formulated intoa pharmaceutical composition in accordance with standard pharmaceuticalpractice. This invention, therefore, also relates to a pharmaceuticalcomposition comprising an effective, non-toxic amount of a compound ofFormula (I) and a pharmaceutically acceptable carrier or diluent.

Compounds of Formula (I), pharmaceutically acceptable salts thereof andpharmaceutical compositions incorporating such may conveniently beadministered by any of the routes conventionally used for drugadministration, for instance, orally, topically, parenterally or byinhalation. The compounds of Formula (I) may be administered inconventional dosage forms prepared by combining a compound of Formula(I) with standard pharmaceutical carriers according to conventionalprocedures. The compounds of Formula (I) may also be administered inconventional dosages in combination with a known, second therapeuticallyactive compound. These procedures may involve mixing, granulating andcompressing or dissolving the ingredients as appropriate to the desiredpreparation. It will be appreciated that the form and character of thepharmaceutically acceptable character or diluent is dictated by theamount of active ingredient with which it is to be combined, the routeof administration and other well-known variables. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like. Similarly, the carrier or diluent may includetime delay material well known to the art, such as glycerylmono-stearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 g. When a liquid carrier is used,the preparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule or nonaqueousliquid suspension.

Compounds of Formula (I) may be administered topically, that is bynon-systemic administration. This includes the application of a compoundof Formula (I) externally to the epidermis or the buccal cavity and theinstillation of such a compound into the ear, eye and nose, such thatthe compound does not significantly enter the blood stream. In contrast,systemic administration refers to oral, intravenous, intraperitoneal andintramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as liniments, lotions, creams, ointmentsor pastes, and drops suitable for administration to the eye, ear ornose. The active ingredient may comprise, for topical administration,from 0.001% to 10% w/w, for instance from 1% to 2% by weight of theformulation. It may however comprise as much as 10% w/w but preferablywill comprise less than 5% w/w, more preferably from 0.1% to 1% w/w ofthe formulation.

Lotions according to the present invention include those suitable forapplication to the skin or eye. An eye lotion may comprise a sterileaqueous solution optionally containing a bactericide and may be preparedby methods similar to those for the preparation of drops. Lotions orliniments for application to the skin may also include an agent tohasten drying and to cool the skin, such as an alcohol or acetone,and/or a moisturizer such as glycerol or an oil such as castor oil orarachis oil.

Creams, ointments or pastes according to the present invention aresemi-solid formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient infinely-divided or powdered form, alone or in solution or suspension inan aqueous or non-aqueous fluid, with the aid of suitable machinery,with a greasy or non-greasy base. The base may comprise hydrocarbonssuch as hard, soft or liquid paraffin, glycerol, beeswax, a metallicsoap; a mucilage; an oil of natural origin such as almond, corn,arachis, castor or olive oil; wool fat or its derivatives or a fattyacid such as stearic or oleic acid together with an alcohol such aspropylene glycol or a macrogel. The formulation may incorporate anysuitable surface active agent such as an anionic, cationic or non-ionicsurfactant such as a sorbitan ester or a polyoxyethylene derivativethereof. Suspending agents such as natural gums, cellulose derivativesor inorganic materials such as silicaceous silicas, and otheringredients such as lanolin, may also be included.

Drops according to the present invention may comprise sterile aqueous oroily solutions or suspensions and may be prepared by dissolving theactive ingredient in a suitable aqueous solution of a bactericidaland/or fungicidal agent and/or any other suitable preservative, andpreferably including a surface active agent. The resulting solution maythen be clarified by filtration, transferred to a suitable containerwhich is then sealed and sterilized by autoclaving or maintaining at98-100° C. for half an hour. Alternatively, the solution may besterilized by filtration and transferred to the container by an aseptictechnique. Examples of bactericidal and fungicidal agents suitable forinclusion in the drops are phenylmercuric nitrate or acetate (0.002%),benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).Suitable solvents for the preparation of an oily solution includeglycerol, diluted alcohol and propylene glycol.

Compounds of Formula (I) may be administered parenterally, that is byintravenous, intramuscular, subcutaneous intranasal, intrarectal,intravaginal or intraperitoneal administration. The subcutaneous andintramuscular forms of parenteral administration are generallypreferred. Appropriate dosage forms for such administration may beprepared by conventional techniques. Compounds of Formula (I) may alsobe administered by inhalation, that is by intranasal and oral inhalationadministration. Appropriate dosage forms for such administration, suchas an aerosol formulation or a metered dose inhaler, may be prepared byconventional techniques.

In one embodiment of the present invention, the agents of the presentinvention are delivered via oral inhalation or intranasaladministration. Appropriate dosage forms for such administration, suchas an aerosol formulation or a metered dose inhaler, may be prepared byconventional techniques.

For administration by inhalation the compounds may be delivered in theform of an aerosol spray presentation from pressurized packs or anebulizer, with the use of a suitable propellant, e.g.dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, a hydrofluoroalkane such as tetrafluoroethaneor heptafluoropropane, carbon dioxide or other suitable gas. In the caseof a pressurized aerosol the dosage unit may be determined by providinga valve to deliver a metered amount. Capsules and cartridges of e.g.gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of a compound of the invention and a suitablepowder base such as lactose or starch.

Dry powder compositions for topical delivery to the lung by inhalationmay, for example, be presented in capsules and cartridges of for examplegelatine or blisters of for example laminated aluminium foil, for use inan inhaler or insufflator. Powder blend formulations generally contain apowder mix for inhalation of the compound of the invention and asuitable powder base (carrier/diluent/excipient substance) such asmono-, di or poly-saccharides (e.g. lactose or starch). Use of lactoseis preferred.

Each capsule or cartridge may generally contain between 20 μg-10 mg ofthe compound of formula (I) optionally in combination with anothertherapeutically active ingredient. Alternatively, the compound of theinvention may be presented without excipients.

Suitably, the packing/medicament dispenser is of a type selected fromthe group consisting of a reservoir dry powder inhaler (RDPI), amulti-dose dry powder inhaler (MDPI), and a metered dose inhaler (MDI).

By reservoir dry powder inhaler (RDPI) it is meant an inhaler having areservoir form pack suitable for comprising multiple (un-metered doses)of medicament in dry powder form and including means for meteringmedicament dose from the reservoir to a delivery position. The meteringmeans may for example comprise a metering cup, which is movable from afirst position where the cup may be filled with medicament from thereservoir to a second position where the metered medicament dose is madeavailable to the patient for inhalation.

By multi-dose dry powder inhaler (MDPI) is meant an inhaler suitable fordispensing medicament in dry powder form, wherein the medicament iscomprised within a multi-dose pack containing (or otherwise carrying)multiple, define doses (or parts thereof) of medicament. In a preferredaspect, the carrier has a blister pack form, but it could also, forexample, comprise a capsule-based pack form or a carrier onto whichmedicament has been applied by any suitable process including printing,painting and vacuum occlusion.

In the case of multi-dose delivery, the formulation can be pre-metered(e.g. as in Diskus, see GB 2242134, U.S. Pat. Nos. 6,632,666, 5,860,419,5,873,360 and 5,590,645 or Diskhaler, see GB 2178965, 2129691 and2169265, U.S. Pat. Nos. 4,778,054, 4,811,731, 5,035,237, the disclosuresof which are hereby incorporated by reference) or metered in use (e.g.as in Turbuhaler, see EP 69715 or in the devices described in U.S. Pat.No. 6,321,747 the disclosures of which are hereby incorporated byreference). An example of a unit-dose device is Rotahaler (see GB2064336 and U.S. Pat. No. 4,353,656, the disclosures of which are herebyincorporated by reference).

The Diskus inhalation device comprises an elongate strip formed from abase sheet having a plurality of recesses spaced along its length and alid sheet hermetically but peelably sealed thereto to define a pluralityof containers, each container having therein an inhalable formulationcontaining a compound of formula (I) or (Ia) preferably combined withlactose. Preferably, the strip is sufficiently flexible to be wound intoa roll. The lid sheet and base sheet will preferably have leading endportions which are not sealed to one another and at least one of thesaid leading end portions is constructed to be attached to a windingmeans. Also, preferably the hermetic seal between the base and lidsheets extends over their whole width. The lid sheet may preferably bepeeled from the base sheet in a longitudinal direction from a first endof the said base sheet.

In one aspect, the multi-dose pack is a blister pack comprising multipleblisters for containment of medicament in dry powder form. The blistersare typically arranged in regular fashion for ease of release ofmedicament there from.

In one aspect, the multi-dose blister pack comprises plural blistersarranged in generally circular fashion on a disc-form blister pack. Inanother aspect, the multi-dose blister pack is elongate in form, forexample comprising a strip or a tape.

In one aspect, the multi-dose blister pack is defined between twomembers peelably secured to one another. U.S. Pat. Nos. 5,860,419,5,873,360 and 5,590,645 describe medicament packs of this general type.In this aspect, the device is usually provided with an opening stationcomprising peeling means for peeling the members apart to access eachmedicament dose. Suitably, the device is adapted for use where thepeelable members are elongate sheets which define a plurality ofmedicament containers spaced along the length thereof, the device beingprovided with indexing means for indexing each container in turn. Morepreferably, the device is adapted for use where one of the sheets is abase sheet having a plurality of pockets therein, and the other of thesheets is a lid sheet, each pocket and the adjacent part of the lidsheet defining a respective one of the containers, the device comprisingdriving means for pulling the lid sheet and base sheet apart at theopening station.

By metered dose inhaler (MDI) it is meant a medicament dispensersuitable for dispensing medicament in aerosol form, wherein themedicament is comprised in an aerosol container suitable for containinga propellant-based aerosol medicament formulation. The aerosol containeris typically provided with a metering valve, for example a slide valve,for release of the aerosol form medicament formulation to the patient.The aerosol container is generally designed to deliver a predetermineddose of medicament upon each actuation by means of the valve, which canbe opened either by depressing the valve while the container is heldstationary or by depressing the container while the valve is heldstationary.

Where the medicament container is an aerosol container, the valvetypically comprises a valve body having an inlet port through which amedicament aerosol formulation may enter said valve body, an outlet portthrough which the aerosol may exit the valve body and an open/closemechanism by means of which flow through said outlet port iscontrollable.

The valve may be a slide valve wherein the open/close mechanismcomprises a sealing ring and receivable by the sealing ring a valve stemhaving a dispensing passage, the valve stem being slidably movablewithin the ring from a valve-closed to a valve-open position in whichthe interior of the valve body is in communication with the exterior ofthe valve body via the dispensing passage.

Typically, the valve is a metering valve. The metering volumes aretypically from 10 to 100 μl, such as 25 μl, 50 μl or 63 μl. Suitably,the valve body defines a metering chamber for metering an amount ofmedicament formulation and an open/close mechanism by means of which theflow through the inlet port to the metering chamber is controllable.Preferably, the valve body has a sampling chamber in communication withthe metering chamber via a second inlet port, said inlet port beingcontrollable by means of an open/close mechanism thereby regulating theflow of medicament formulation into the metering chamber.

The valve may also comprise a ‘free flow aerosol valve’ having a chamberand a valve stem extending into the chamber and movable relative to thechamber between dispensing and non-dispensing positions. The valve stemhas a configuration and the chamber has an internal configuration suchthat a metered volume is defined there between and such that duringmovement between is non-dispensing and dispensing positions the valvestem sequentially: (i) allows free flow of aerosol formulation into thechamber, (ii) defines a closed metered volume for pressurized aerosolformulation between the external surface of the valve stem and internalsurface of the chamber, and (iii) moves with the closed metered volumewithin the chamber without decreasing the volume of the closed meteredvolume until the metered volume communicates with an outlet passagethereby allowing dispensing of the metered volume of pressurized aerosolformulation. A valve of this type is described in U.S. Pat. No.5,772,085. Additionally, intra-nasal delivery of the present compoundsis effective.

To formulate an effective pharmaceutical nasal composition, themedicament must be delivered readily to all portions of the nasalcavities (the target tissues) where it performs its pharmacologicalfunction. Additionally, the medicament should remain in contact with thetarget tissues for relatively long periods of time. The longer themedicament remains in contact with the target tissues, the medicamentmust be capable of resisting those forces in the nasal passages thatfunction to remove particles from the nose. Such forces, referred to as‘mucociliary clearance’, are recognised as being extremely effective inremoving particles from the nose in a rapid manner, for example, within10-30 minutes from the time the particles enter the nose.

Other desired characteristics of a nasal composition are that it mustnot contain ingredients which cause the user discomfort, that it hassatisfactory stability and shelf-life properties, and that it does notinclude constituents that are considered to be detrimental to theenvironment, for example ozone depletors.

A suitable dosing regime for the formulation of the present inventionwhen administered to the nose would be for the patient to inhale deeplysubsequent to the nasal cavity being cleared. During inhalation theformulation would be applied to one nostril while the other is manuallycompressed. This procedure would then be repeated for the other nostril.

In one embodiment, the means for applying a formulation of the presentinvention to the nasal passages is by use of a pre-compression pump.Most preferably, the pre-compression pump will be a VP7 modelmanufactured by Valois SA. Such a pump is beneficial as it will ensurethat the formulation is not released until a sufficient force has beenapplied, otherwise smaller doses may be applied. Another advantage ofthe pre-compression pump is that atomisation of the spray is ensured asit will not release the formulation until the threshold pressure foreffectively atomising the spray has been achieved. Typically, the VP7model may be used with a bottle capable of holding 10-50 ml of aformulation. Each spray will typically deliver 50-100 μl of such aformulation, therefore, the VP7 model is capable of providing at least100 metered doses.

Spray compositions for topical delivery to the lung by inhalation mayfor example be formulated as aqueous solutions or suspensions or asaerosols delivered from pressurised packs, such as a metered doseinhaler, with the use of a suitable liquefied propellant. Aerosolcompositions suitable for inhalation can be either a suspension or asolution and generally contain the compound of Formula (I) optionally incombination with another therapeutically active ingredient and asuitable propellant such as a fluorocarbon or hydrogen-containingchlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes,e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetra-fluoroethane, especially 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. Carbon dioxideor other suitable gas may also be used as propellant. The aerosolcomposition may be excipient free or may optionally contain additionalformulation excipients well known in the art such as surfactants, e.g.,oleic acid or lecithin and cosolvents, e.g. ethanol. Pressurisedformulations will generally be retained in a canister (e.g. an aluminiumcanister) closed with a valve (e.g. a metering valve) and fitted into anactuator provided with a mouthpiece.

Medicaments for administration by inhalation desirably have a controlledparticle size. The optimum particle size for inhalation into thebronchial system is usually 1-10 μm, preferably 2-5 μm. Particles havinga size above 20 μm are generally too large when inhaled to reach thesmall airways. To achieve these particle sizes the particles of theactive ingredient as produced may be size reduced by conventional meanse.g., by micronization. The desired fraction may be separated out by airclassification or sieving. Suitably, the particles will be crystallinein form. When an excipient such as lactose is employed, generally, theparticle size of the excipient will be much greater than the inhaledmedicament within the present invention. When the excipient is lactoseit will typically be present as milled lactose, wherein not more than85% of lactose particles will have a MMD of 60-90 μm and not less than15% will have a MMD of less than 15 μm.

Intranasal sprays may be formulated with aqueous or non-aqueous vehicleswith the addition of agents such as thickening agents, buffer salts oracid or alkali to adjust the pH, isotonicity adjusting agents oranti-oxidants.

Solutions for inhalation by nebulization may be formulated with anaqueous vehicle with the addition of agents such as acid or alkali,buffer salts, isotonicity adjusting agents or antimicrobials. They maybe sterilised by filtration or heating in an autoclave, or presented asa non-sterile product.

For all methods of use disclosed herein for the compounds of Formula(I), the daily oral dosage regimen will preferably be from about 0.05 toabout 80 mg/kg of total body weight, preferably from about 0.1 to 30mg/kg, more preferably from about 0.5 mg to 15 mg/kg, administered inone or more daily doses. The daily parenteral dosage regimen about 0.1to about 80 mg/kg of total body weight, preferably from about 0.2 toabout 30 mg/kg, and more preferably from about 0.5 mg to 15 mg/kg,administered in one or more daily doses. The daily topical dosageregimen will preferably be from 0.01 mg to 150 mg, administered one tofour times daily. The daily inhalation dosage regimen will preferably befrom about 0.05 microgram/kg to about 1 mg/kg per day, more preferablyfrom about 0.2 microgram/kg to about 20 microgram/kg, administered inone or more daily doses. It will also be recognized by one of skill inthe art that the optimal quantity and spacing of individual dosages of acompound of Formula (I) or a pharmaceutically acceptable salt thereofwill be determined by the nature and extent of the condition beingtreated, the form, route and site of administration, and the particularpatient being treated, and that such optimums can be determined byconventional techniques. It will also be appreciated by one of skill inthe art that the optimal course of treatment, i.e., the number of dosesof a compound of Formula (I) or a pharmaceutically acceptable saltthereof given per day for a defined number of days, can be ascertainedby those skilled in the art using conventional course of treatmentdetermination tests.

The novel compounds of Formula (I) may also be used in association withthe veterinary treatment of mammals, other than humans, in need ofinhibition of CSBP/p38 or cytokine inhibition or production. Inparticular, CSBP/p38 mediated diseases for treatment, therapeutically orprophylactically, in animals include disease states such as those notedherein in the Methods of Treatment section, but in particular viralinfections. Examples of such viruses include, but are not limited to,lentivirus infections such as, equine infectious anaemia virus, caprinearthritis virus, visna virus, or maedi virus or retrovirus infections,such as but not limited to feline immunodeficiency virus (FIV), bovineimmunodeficiency virus, or canine immunodeficiency virus or otherretroviral infections.

Another aspect of the present invention is a method of treating, thecommon cold or respiratory viral infection caused by human rhinovirus(HRV), other enteroviruses, coronavirus, influenza virus, parainfluenzavirus, respiratory syncytial virus, or adenovirus in a human in needthereof which method comprises administering to said human an effectiveamount of a CBSP/p38 inhibitor.

Another aspect of the present invention is a method of treating,including prophylaxis, of influenza induced pneumonia in a human in needthereof which method comprises administering to said human an effectiveamount of a CBSP/p38 inhibitor

The present invention also relates to the use of the CSBP/p38 kinaseinhibitor for the treatment, including prophylaxis, of inflammationassociated with a viral infection of a human rhinovirus (HRV), otherenteroviruses, coronavirus, influenza virus, parainfluenza virus,respiratory syncytial virus, or adenovirus.

In particular, the present invention is directed to the treatment of aviral infection in a human, which is caused by the human rhinovirus(HRV), other enterovirus, coronavirus, influenza virus, parainfluenzavirus, respiratory syncytial virus, or an adenovirus. In particular theinvention is directed to respiratory viral infections that exacerbateasthma (induced by such infections), chronic bronchitis, chronicobstructive pulmonary disease, otitis media, and sinusitis. Whileinhibiting IL-8 or other cytokines may be beneficial in treating arhinovirus may be known, the use of an inhibitor of the p38 kinase fortreating HRV or other respiratory viral infections causing the commoncold is believed novel.

It should be noted that the respiratory viral infection treated hereinmay also be associated with a secondary bacterial infection, such asotitis media, sinusitis, or pneumonia.

For use herein treatment may include prophylaxis for use in a treatmentgroup susceptible to such infections. It may also include reducing thesymptoms of, ameliorating the symptoms of, reducing the severity of,reducing the incidence of, or any other change in the condition of thepatient, which improves the therapeutic outcome.

It should be noted that the treatment herein is not directed to theelimination or treatment of the viral organism itself but is directed totreatment of the respiratory viral infection that exacerbates otherdiseases or symptoms of disease, such as asthma (induced by suchinfections), chronic bronchitis, chronic obstructive pulmonary disease,otitis media, and sinusitis.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavouring agents, or those for inhalation may include carriers,such as lactose.

The compounds and pharmaceutical formulations according to the inventionmay be used in combination with or include one or more other therapeuticagents, for example selected from anti-inflammatory agents,anticholinergic agents (particularly an M₁, M₂, M₁/M₂ or M₃ receptorantagonist), β₂-adrenoreceptor agonists, antiinfective agents (e.g.antibiotics, antivirals), or antihistamines. The invention thusprovides, in a further aspect, a combination comprising a compound offormula (I) or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof together with one or moreother therapeutically active agents, for example selected from ananti-inflammatory agent (for example a corticosteroid or an NSAID), ananticholinergic agent, β₂-adrenoreceptor agonist, an antiinfective agent(e.g. an antibiotic or an antiviral), or an antihistamine. One aspect ofthe present invention are combinations comprising a compound of Formula(I) or a pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof together with a corticosteroid, and/or ananticholinergic, and/or a PDE-4 inhibitor. Preferred combinations arethose comprising one or two other therapeutic agents.

It will be clear to a person skilled in the art that, where appropriate,the other therapeutic ingredient(s) may be used in the form of salts,(e.g. as alkali metal or amine salts or as acid addition salts), orprodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g.hydrates) to optimise the activity and/or stability and/or physicalcharacteristics (e.g. solubility) of the therapeutic ingredient. It willbe clear also that where appropriate, the therapeutic ingredients may beused in optically pure form.

One suitable combination of the present invention comprises of compoundof the invention together with a β₂-adrenoreceptor agonist.

Examples of β₂-adrenoreceptor agonists include salmeterol (which may bea racemate or a single enantiomer, such as the R-enantiomer),salbutamol, formoterol, salmefamol, fenoterol or terbutaline and saltsthereof, for example the xinafoate salt of salmeterol, the sulphate saltor free base of salbutamol or the fumarate salt of formoterol.Long-acting β₂-adrenoreceptor agonists are preferred, especially thosehaving a therapeutic effect over a 24 hour period, such as salmeterol orformoterol.

Suitable long acting β₂-adrenoreceptor agonists include those describedin WO02/66422A, WO02/270490, WO02/076933, WO03/024439, WO03/072539, WO03/091204, WO04/016578, WO04/022547, WO04/037807, WO04/037773,WO04/037768, WO04/039762, WO04/039766, WO01/42193 and WO03/042160, whosedisclosures are incorporated by reference herein.

Preferred long-acting β₂-adrenoreceptor agonists are:

-   3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;-   3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamide;-   4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;-   4-{(1R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;-   N-[2-hydroxyl-5-[(1R)-1-hydroxy-2-[[2-4-[[(2R)-2-hydroxy-2-phenylethyl]amino]phenyl]ethyl]amino]ethyl]phenyl]foramide,    and-   N-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine.

Suitable anti-inflammatory agents include corticosteroids. Suitablecorticosteroids which may be used in combination with the compounds ofthe invention are those oral and inhaled corticosteroids and theirpro-drugs which have anti-inflammatory activity. Examples include methylprednisolone, prednisolone, dexamethasone, fluticasone propionate,6═,9═-difluoro-17═-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-35-yl) ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-(1-methylcylopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester, 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carboxylicacid cyanomethyl ester, beclomethasone esters (such as the 17-propionateester or the 17,21-dipropionate ester), budesonide, flunisolide,mometasone esters (such as the furoate ester), triamcinolone acetonide,rofleponide, ciclesonide,(16α,17-[[(R)-cyclohexylmethylene]bis(oxy)]-11β,21-dihydroxy-pregna-1,4-diene-3,20-dione),butixocort propionate, RPR-106541, and ST-126. Preferred corticosteroidsinclude fluticasone propionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester and6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester, more preferably6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.

Non-steroidal compounds having glucocorticoid agonism that may possessselectivity for transrepression over transactivation and that may beuseful in combination therapy include those covered in the followingpatents: WO03/082827, WO01/10143, WO098/54159, WO04/005229, WO04/009016,WO04/009017, WO04/018429, WO03/104195, WO03/082787, WO03/082280,WO03/059899, WO03/101932, WO02/02565, WO01/16128, WO00/66590,WO03/086294, WO04/026248, WO03/061651, WO03/08277.

Suitable anti-inflammatory agents include non-steroidalanti-inflammatory drugs (NSAID's).

Suitable NSAID's include sodium cromoglycate, nedocromil sodium,phosphodiesterase (PDE) inhibitors (for example, theophylline, PDE4inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists,inhibitors of leukotriene synthesis (for example, montelukast), iNOSinhibitors, tryptase and elastase inhibitors, beta-2 integrinantagonists and adenosine receptor agonists or antagonists (for example,adenosine 2a agonists), cytokine antagonists (for example, chemokineantagonists, such as a CCR3 antagonist) or inhibitors of cytokinesynthesis, or 5-lipoxygenase inhibitors. Suitable otherβ₂-adrenoreceptor agonists include salmeterol (for example, as thexinafoate), salbutamol (for example, as the sulphate or the free base),formoterol (for example, as the fumarate), fenoterol or terbutaline andsalts thereof. An iNOS (inducible nitric oxide synthase inhibitor) ispreferably for oral administration. Suitable iNOS inhibitors includethose disclosed in WO93/13055, WO98/30537, WO02/50021, WO95/34534 andWO99/62875. Suitable CCR3 inhibitors include those disclosed inWO02/26722.

Another embodiment of the invention is the use of the compound of aFormula (I) or (Ia) in combination with a phosphodiesterase 4 (PDE4)inhibitor or a mixed PDE3/PDE4 inhibitor. The PDE4-specific inhibitoruseful in this aspect of the invention may be any compound that is knownto inhibit the PDE4 enzyme or which is discovered to act as a PDE4inhibitor, and which are only PDE4 inhibitors, not compounds whichinhibit other members of the PDE family as well as PDE4. Generally it ispreferred to use a PDE4 inhibitor which has an IC₅₀ ratio of about 0.1or greater as regards the IC₅₀ for the PDE4 catalytic form which bindsrolipram with a high affinity divided by the IC₅₀ for the form whichbinds rolipram with a low affinity. For the purposes of this disclosure,the cAMP catalytic site which binds R and S rolipram with a low affinityis denominated the “low affinity” binding site (LPDE 4) and the otherform of this catalytic site which binds rolipram with a high affinity isdenominated the “high affinity” binding site (HPDE 4). This term “HPDE4”should not be confused with the term “hPDE4” which is used to denotehuman PDE4.

A method for determining IC₅₀s ratios is set out in U.S. Pat. No.5,998,428 which is incorporated herein in full by reference as thoughset out herein. See also PCT application WO 00/51599 for anotherdescription of said assay. In one embodiment, PDE4 inhibitors of use inthis invention will be those compounds which have a salutary therapeuticratio, i.e., compounds which preferentially inhibit cAMP catalyticactivity where the enzyme is in the form that binds rolipram with a lowaffinity, thereby reducing the side effects which apparently are linkedto inhibiting the form which binds rolipram with a high affinity.Another way to state this is that the compounds will have an IC₅₀ ratioof about 0.1 or greater as regards the IC₅₀ for the PDE4 catalytic formwhich binds rolipram with a high affinity divided by the IC₅₀ for theform which binds rolipram with a low affinity.

A further refinement of this standard is that of one wherein the PDE4inhibitor has an IC₅₀ ratio of about 0.1 or greater; said ratio is theratio of the IC₅₀ value for competing with the binding of 1 nM of[³H]R-rolipram to a form of PDE4 which binds rolipram with a highaffinity over the IC₅₀ value for inhibiting the PDE4 catalytic activityof a form which binds rolipram with a low affinity using 1 μM[³H]-cAMPas the substrate.

Suitable PDE compounds are cis4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];these are examples of compounds which bind preferentially to the lowaffinity binding site and which have an IC₅₀ ratio of 0.1 or greater.

Other compounds of interest include: Compounds set out in U.S. Pat. No.5,552,438 issued 3 Sep. 1996; this patent and the compounds it disclosesare incorporated herein in full by reference. The compound of particularinterest, which is disclosed in U.S. Pat. No. 5,552,438, iscis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomalast) and its salts, esters, pro-drugs orphysical forms; AWD-12-281 from elbion (Hofgen, N. et al. 15th EFMC Int.Symp. Med. Chem. (September 6-10, Edinburgh) 1998, Abst. P.98; CASreference No. 247584020-9); a 9-benzyladenine derivative nominatedNCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; abenzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787) andattributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakkoin WO99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, L.J. et al. Eur Resp J [Annu Cong Eur Resp Soc (September 19-23, Geneva)1998] 1998, 12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No162401-32-3) and a pthalazinone (WO99/47505, the disclosure of which ishereby incorporated by reference) from Byk-Gulden; Pumafentrine,(−)-p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamidewhich is a mixed PDE3/PDE4 inhibitor which has been prepared andpublished on by Byk-Gulden, now Altana; arofylline under development byAlmirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (TanabeSeiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284(1): 162), andT2585. Other possible PDE-4 and mixed PDE3/PDE4 inhibitors include thoselisted in WO01/13953, the disclosure of which is hereby incorporated byreference.

Suitable anticholinergic agents are those compounds that act asantagonists at the muscarinic receptor, in particular those compoundswhich are antagonists of the M₁ and M₂ receptors. Exemplary compoundsinclude the alkaloids of the belladonna plants as illustrated by thelikes of atropine, scopolamine, homatropine, hyoscyamine; thesecompounds are normally administered as a salt, being tertiary amines.These drugs, particularly the salt forms, are readily available from anumber of commercial sources or can be made or prepared from literaturedata via, to wit:

Atropine—CAS-51-55-8 or CAS-51-48-1 (anhydrous form), atropinesulfate—CAS-5908-99-6; atropine oxide—CAS-4438-22-6 or its HClsalt—CAS-4574-60-1 and methylatropine nitrate—CAS-52-88-0;Homatropine—CAS-87-00-3, hydrobromide salt—CAS-51-56-9, methylbromidesalt—CAS-80-49-9;Hyoscyamine (d, l)—CAS-101-31-5, hydrobromidesalt—CAS-306-03-6 and sulfate salt—CAS-6835-16-1; andScopolamine—CAS-51-34-3, hydrobromide salt—CAS-6533-68-2, methylbromidesalt—CAS-155-41-9.

Suitable anticholinergics for use herein include, but are not limitedto, ipratropium (e.g. as the bromide), sold under the name Atrovent,oxitropium (e.g. as the bromide) and tiotropium (e.g. as the bromide)(CAS-139404-48-1). Also of interest are: methantheline (CAS-53-46-3),propantheline bromide (CAS-50-34-9), anisotropine methyl bromide orValpin 50 (CAS-80-50-2), clidinium bromide (Quarzan, CAS-3485-62-9),copyrrolate (Robinul), isopropamide iodide (CAS-71-81-8), mepenzolatebromide (U.S. Pat. No. 2,918,408), tridihexethyl chloride (Pathilone,CAS-4310-35-4), and hexocyclium methylsulfate (Tral, CAS-115-63-9). Seealso cyclopentolate hydrochloride (CAS-5870-29-1), tropicamide(CAS-1508-75-4), trihexyphenidyl hydrochloride (CAS-144-11-6),pirenzepine (CAS-29868-97-1), telenzepine (CAS-80880-90-9), AF-DX 116,or methoctramine, and the compounds disclosed in WO 01/04118, thedisclosure of which is hereby incorporated by reference.

Other suitable anticholinergic agents include compounds of formula(XXI), which are disclosed in U.S. patent application 60/487,981:

in which the preferred orientation of the alkyl chain attached to thetropane ring is endo;

-   R³¹ and R³² are, independently, selected from the group consisting    of straight or branched chain lower alkyl groups having preferably    from 1 to 6 carbon atoms, cycloalkyl groups having from 5 to 6    carbon atoms, cycloalkyl-alkyl having 6 to 10 carbon atoms,    2-thienyl, 2-pyridyl, phenyl, phenyl substituted with an alkyl group    having not in excess of 4 carbon atoms and phenyl substituted with    an alkoxy group having not in excess of 4 carbon atoms;-   X⁻ represents an anion associated with the positive charge of the N    atom.-   X⁻ includes, but is not limited to chloride, bromide, iodide,    sulfate, benzene sulfonate, and toluene sulfonate.-   Suitably, this includes the following exemplifications:-   (3-endo)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane    bromide;-   (3-endo)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane    bromide;-   (3-endo)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane    4-methylbenzenesulfonate;-   (3-endo)-8,8-dimethyl-3-[2-phenyl-2-(2-thienyl)ethenyl]-8-azoniabicyclo[3.2.1]octane    bromide; and/or-   (3-endo)-8,8-dimethyl-3-[2-phenyl-2-(2-pyridinyl)ethenyl]-8-azoniabicyclo[3.2.1]octane    bromide.

Further suitable anticholinergic agents include compounds of formula(XXII) or (XOH), which are disclosed in U.S. patent application60/511,009:

wherein:

-   the H atom indicated is in the exo position;-   R⁴¹ represents an anion associated with the positive charge of the N    atom., R⁴¹ may be, but is not limited to, chloride, bromide, iodide,    sulfate, benzene sulfonate and toluene sulfonate;-   R⁴² and R⁴³ are independently selected from the group consisting of    straight or branched chain lower alkyl groups (having preferably    from 1 to 6 carbon atoms), cycloalkyl groups (having from 5 to 6    carbon atoms), cycloalkyl-alkyl (having 6 to 10 carbon atoms),    heterocycloalkyl (having 5 to 6 carbon atoms) and N or O as the    heteroatom, heterocycloalkyl-alkyl (having 6 to10 carbon atoms) and    N or O as the heteroatom, aryl, optionally substituted aryl,    heteroaryl, and optionally substituted heteroaryl;-   R⁴⁴ is selected from the group consisting of (C₁-C₆)alkyl,    (C₃-C₁₂)cycloalkyl, (C₃-C₇)heterocycloalkyl,    (C₁-C₆)alkyl(C₃-C₁₂)cycloalkyl, (C₁-C₆)alkyl(C₃-C₇)heterocycloalkyl,    aryl, heteroaryl, (C₁-C₆)alkyl-aryl, (C₁-C₆)alkyl-heteroaryl, —OR⁴⁵,    —CH₂OR⁴⁵, —CH₂OH, —CN, —CF₃, —CH₂O(CO)R⁴⁶, —CO₂R⁴⁷, —CH₂NH₂,    —CH₂N(R⁴⁷)SO₂R⁴⁵, —SO₂N(R⁴⁷)(R⁴⁸), —CON(R⁴⁷)(R⁴⁸),    —CH₂N(R⁴⁸)CO(R⁴⁶), —CH₂N(R⁴⁸)SO₂(R⁴⁶), —CH₂N(R⁴⁸)CO₂(R⁴⁵),    —CH₂N(R⁴⁸)CONH(R⁴⁷);-   R⁴⁵ is selected from the group consisting of (C₁-C₆)alkyl,    (C₁-C₆)alkyl(C₃-C₁₂)cycloalkyl, (C₁-C₆)alkyl(C₃-C₇)heterocycloalkyl,    (C₁-C₆)alkyl-aryl, (C₁-C₆)alkyl-heteroaryl;-   R⁴⁶ is selected from the group consisting of (C₁-C₆)alkyl,    (C₃-C₁₂)cycloalkyl, (C₃-C₇)heterocycloalkyl,    (C₁-C₆)alkyl(C₃-C₁₂)cycloalkyl, (C₁-C₆)alkyl(C₃-C₇)heterocycloalkyl,    aryl, heteroaryl, (C₁-C₆)alkyl-aryl, (C₁-C₆)alkyl-heteroaryl;-   R⁴⁷ and R⁴⁸ are, independently, selected from the group consisting    of H, (C₁-C₆)alkyl, (C₃-C₁₂)cycloalkyl, (C₃-C₇)heterocycloalkyl,    (C₁-C₆)alkyl(C₃-C₁₂)cycloalkyl, (C₁-C₆)alkyl(C₃-C₇)heterocycloalkyl,    (C₁-C₆)alkyl-aryl, and (C₁-C₆)alkyl-heteroaryl.-   Representative examples included are:-   (Endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionitrile;-   (Endo)-8-methyl-3-(2,2,2-triphenyl-ethyl)-8-aza-bicyclo[3.2.1]octane;-   3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamide;-   3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionic    acid;-   (Endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   (Endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    bromide;-   3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propan-1-ol;-   N-Benzyl-3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamide;-   (Endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   1-Benzyl-3-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;-   1-Ethyl-3-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;-   N-[3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-acetamide;-   N-[3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-benzamide;-   3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-di-thiophen-2-yl-propionitrile;-   (Endo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   N-[3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-benzenesulfonamide;-   [3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;-   N-[3-((Endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-methanesulfonamide;    and/or-   (Endo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    bromide.-   Preferred compounds useful in the present invention include:-   (Endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   (Endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   (Endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    bromide;-   (Endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   (Endo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide; and/or-   (Endo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    bromide.

Suitable antihistamines (also referred to as H₁-receptor antagonists)include any one or more of the numerous antagonists known which inhibitH₁-receptors, and are safe for human use. All are reversible,competitive inhibitors of the interaction of histamine withH₁-receptors. The majority of these inhibitors, mostly first generationantagonists, have a core structure, which can be represented by thefollowing formula:

This generalized structure represents three types of antihistaminesgenerally available: ethanolamines, ethylenediamines, and alkylamines.In addition, other first generation antihistamines include those whichcan be characterized as based on piperizine and phenothiazines. Secondgeneration antagonists, which are non-sedating, have a similarstructure-activity relationship in that they retain the core ethylenegroup (the alkylamines) or mimic the tertiary amine group withpiperizine or piperidine.

-   Exemplary antagonists are as follows:-   Ethanolamines: carbinoxamine maleate, clemastine fumarate,    diphenylhydramine hydrochloride, and dimenhydrinate.-   Ethylenediamines: pyrilamine amleate, tripelennamine HCl, and    tripelennamine citrate.-   Alkylamines: chloropheniramine and its salts such as the maleate    salt, and acrivastine.-   Piperazines: hydroxyzine HCl, hydroxyzine pamoate, cyclizine HCl    cyclizine lactate, meclizine HCl, and cetirizine HCl.-   Piperidines: Astemizole, levocabastine HCl, loratadine or its    descarboethoxy analogue, and terfenadine and fexofenadine    hydrochloride or another pharmaceutically acceptable salt.

Azelastine hydrochloride is yet another H₁ receptor antagonist which maybe used in combination with a PDE4 inhibitor.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with aphysiologically acceptable diluent or carrier represent a further aspectof the invention.

The individual compounds of such combinations may be administered eithersequentially or simultaneously in separate or combined pharmaceuticalformulations. Appropriate doses of known therapeutic agents will bereadily appreciated by those skilled in the art.

The invention will now be described by reference to the followingbiological examples which are merely illustrative and are not to beconstrued as a limitation of the scope of the present invention.

Biological Examples

The cytokine-inhibiting effects of compounds of the present inventionmay be determined by the following in vitro assays:

Assays for Interleukin-1 (IL-1beta), Interleukin-8 (IL-8), and TumourNecrosis Factor (TNFalpha) are well known in the art, and may be foundin a number of publications, and patents. Representative suitable assaysfor use herein are described in Adams et al., U.S. Pat. No. 5,593,992,whose disclosure is incorporated by reference in its entirety.

It is recognized that the respective assays herein may have been runmultiple times for particular compounds of Formula (I) or (Ia), etc. asdescribed herein. The determination of activity, as reported in theseassays, will be based upon a mean or median of these values.

Interleukin-1 (IL-1)

Human peripheral blood monocytes are isolated and purified from eitherfresh blood preparations from volunteer donors, or from blood bank buffycoats, according to the procedure of Colotta et al, J Immunol, 132, 936(1984), or another suitable procedure such as positive selectionselection using MACS CD14+ beads. These monocytes (1×10⁶) are plated in24, 48, 96 or 384-well plates at a concentration of 1-2 million/ml perwell. The cells are allowed to adhere for 2 hours, after which timenon-adherent cells can be removed by gentle washing. Test compounds arethen added to the cells for 1 h before the addition oflipopolysaccharide (50-200 ng/ml), and the cultures are incubated at 37°C. for an additional 24 h. At the end of this period, culturesupernatants are removed and clarified of cells and all debris. IL-1betalevels in the cell-free supernatant are then determined by enzyme-linkedimmunoassay (ELISA) or other antibody based procedure.

In Vivo TNF Assay:

(1) Griswold et al., Drugs Under Exp. and Clinical Res., XIX (6),243-248 (1993); or

(2) Boehm, et al., Journal Of Medicinal Chemistry 39, 3929-3937 (1996)whose disclosures are incorporated by reference herein in theirentirety.

LPS-Induced TNFα Production in Mice and Rats

In order to evaluate in vivo inhibition of LPS-induced TNFα productionin rodents, both mice or rats are injected with LPS.

Mouse Method

Male Balb/c mice from Charles River Laboratories are pretreated (30minutes) with compound or vehicle. After the 30 min. pretreat time, themice are given LPS (lipopolysaccharide from Esherichia coli Serotype055-B5, Sigma Chemical Co., St Louis, Mo.) 25 ug/mouse in 25 ulphosphate buffered saline (pH 7.0) intraperitoneally. Two hours laterthe mice are killed by CO₂ inhalation and blood samples are collected byexsanguination into heparinized blood collection tubes and stored onice. The blood samples are centrifuged and the plasma collected andstored at −20° C. until assayed for TNFα by ELISA.

Rat Method

Male Lewis rats from Charles River Laboratories are pretreated atvarious times with compound or vehicle. After a determined pretreattime, the rats are given LPS (lipopolysaccharide from Esherichia coliSerotype 055-B5, Sigma Chemical Co., St Louis, Mo.) 3.0 mg/kgintraperitoneally. The rats are killed by CO₂ inhalation and heparinizedwhole blood is collected from each rat by cardiac puncture 90 minutesafter the LPS injection. The blood samples are centrifuged and theplasma collected for analysis by ELISA for TNFα levels.

ELISA Method

TNFα levels were measured using a sandwich ELISA, Olivera et al., Circ.Shock, 37, 301-306, (1992), whose disclosure is incorporated byreference in its entirety herein, using a hamster monoclonal antimurineTNFα (Genzyme, Boston, Mass.) as the capture antibody and a polyclonalrabbit antimurine TNFa (Genzyme) as the second antibody. For detection,a peroxidase-conjugated goat antirabbit antibody (Pierce, Rockford,Ill.) was added, followed by a substrate for peroxidase (1 mg/mlorthophenylenediamine with 1% urea peroxide). TNFα levels in the plasmasamples from each animal were calculated from a standard curve generatedwith recombinant murine TNFα (Genzyme).

LPS-Stimulated Cytokine Production in Human Whole Blood

-   Assay: Test compound concentrations were prepared at 10×    concentrations and LPS prepared at 1 ug/ml (final conc. of 50 ng/ml    LPS) and added in 50 uL volumes to 1.5 mL eppendorf tubes.    Heparinized human whole blood was obtained from healthy volunteers    and was dispensed into eppendorf tubes or multiwell plates    containing compounds and LPS in 0.2-0.4 mL volumes and the tubes    incubated at 37 C. In some studies, compound was incubated with    blood for up to 30 min prior to addition of LPS. Following a 4 hour    incubation, the tubes or plates were centrifuged to remove cells and    plasma was withdrawn and frozen at −80 C.-   Cytokine measurement: IL-1beta and/or TNFalpha were quantified using    a standardized ELISA, or similar technology. Concentrations of    IL-1beta or TNFalpha were determined from standard curves of the    appropriate cytokine and IC50 values for test compound    (concentration that inhibited 50% of LPS-stimulated cytokine    production) were calculated by linear regression analysis.

Results

Compounds would be considered active in this assay if they demonstrateda IC50 of less than 10 uM up to about an IC50 of less than 0.0001 uM.

Representative compounds of Formula (I) and (Ia) as described inExamples 7(c), 8(c), 9, 10(e), 11, 13, 14, 17, 18, 23(c) and (e), 24,26, 28, 29(c), 53, 58, 69-72, 74-76, 78, 91, 115, 118(c), 119, 121, 123,124, 126, 127, 130, 131, 133, 136-140, 142, 144, 146, 163(a) and (c),165-167, 169-176, 180-181, 184, 192, 205, 206, 211, 213-219, and 223,224 were tested in the above assay and found active.

Compounds of Examples 66-68, 73, 117, 128-129, 141, 143, 161, 162,163(b), and 226 demonstrated an IC50 of greater than 1.0 uM in thisassay. Example 111(c) upon multiple runs provided a range of data,ranging from an IC50 of 0.040 uM to an IC50 of greater than 0.1 uM inthis assay. While these compounds were found to be inhibit greater than50% at a 1 uM of TNF-alpha, some of these compounds would be expectedupon retesting with increasing concentrations to reach 50% inhibition.

CSBP/p38 Kinase Assay:

This assay measures the CSBP/p38-catalyzed transfer of ³²P from[a-³²P]ATP to threonine residue in an epidermal growth factor receptor(EGFR)-derived peptide (T669) with the following sequence:KRELVEPLTPSGEAPNQALLR (residues 661-681). (See Gallagher et al.,“Regulation of Stress Induced Cytokine Production by PyridinylImidazoles: Inhibition of CSBP Kinase”, BioOrganic & MedicinalChemistry, 1997, 5, 49-64).

Reactions were carried in round bottom 96 well plate (from Corning) in a30 ml volume. Reactions contained (in final concentration): 25 mM Hepes,pH 7.5; 8 mM MgCl₂; 0.17 mM ATP (the Km_([ATp]) of p38 (see Lee et al.,Nature 300, n72 pg. 639-746 (December 1994)); 2.5 uCi of [g-32P]ATP; 0.2mM sodium orthovanadate; 1 mM DTT; 0.1% BSA; 10% glycerol; 0.67 mM T669peptide; and 2-4 nM of yeast-expressed, activated and purified p38.Reactions were initiated by the addition of [gamma-32P]Mg/ATP, andincubated for 25 min. at 37° C. Inhibitors (dissolved in DMSO) wereincubated with the reaction mixture on ice for 30 minutes prior toadding the 32P-ATP. Final DMSO concentration was 0.16%. Reactions wereterminated by adding 10 ul of 0.3 M phosphoric acid, and phosphorylatedpeptide was isolated from the reactions by capturing it on p81phosphocellulose filters. Filters were washed with 75 mM phosphoricacids, and incorporated 32P was quantified using beta scintillationcounter. Under these conditions, the specific activity of p38 was400-450 pmol/pmol enzyme, and the activity was linear for up to 2 hoursof incubation. The kinase activity values were obtained aftersubtracting values generated in the absence of substrate which were10-15% of total values.

Fluorescence Anisotropy Kinase Binding Assay—Standard Volume

The kinase enzyme, fluorescent ligand and a variable concentration oftest compound are incubated together to reach thermodynamic equilibriumunder conditions such that in the absence of test compound thefluorescent ligand is significantly (>50%) enzyme bound and in thepresence of a sufficient concentration (>10×K_(i)) of a potent inhibitorthe anisotropy of the unbound fluorescent ligand is measurably differentfrom the bound value.

The concentration of kinase enzyme should preferably be ≧2×K_(f). Theconcentration of fluorescent ligand required will depend on theinstrumentation used, and the fluorescent and physicochemicalproperties. The concentration used must be lower than the concentrationof kinase enzyme, and preferably less than half the kinase enzymeconcentration.

The fluorescent ligand is the following compound:

which is derived from5-[2-(4-aminomethylphenyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-2-chlorophenoland rhodamine green.

Recombinant human p38a was expressed as a GST-tagged protein. Toactivate this protein, 3.5 μM unactivated p38α was incubated in 50 mMTris-HCl pH 7.5, 0.1 mM EGTA, 0.1% 2-mercaptoethanol, 0.1mM sodiumvanadate, 10 mM MgAc, 0.1 mM ATP with 200 nM MBP-MKK6 DD at 30 degreesfor 30 mins. Following activation p38α was re-purified and the activityassessed using a standard filter-binding assay.

-   Protocol: All components are dissolved in buffer of composition 62.5    mM HEPES, pH 7.5, 1.25 mM CHAPS, 1 mM DTT, 12.5 mM MgCl₂ with final    concentrations of 12 nM p38α and 5 nM fluorescent ligand. 30 μl of    this reaction mixture is added to wells containing 1 μl of various    concentrations of test compound (0.28 nM-16.6 μM final) or DMSO    vehicle (3% final) in NUNC 384 well black microtitre plate and    equilibrated for 30-60 mins at room temperature. Fluorescence    anisotropy is read in Molecular Devices Acquest (excitation 485    nm/emission 535 nm).-   Definitions: Ki=dissociation constant for inhibitor binding    -   Kf=dissociation constant for fluorescent ligand binding

Fluorescence Anisotropy Kinase Binding Low Volume Assay

The kinase enzyme, fluorescent ligand and a variable concentration oftest compound are incubated together to reach thermodynamic equilibriumunder conditions such that in the absence of test compound thefluorescent ligand is significantly (>50%) enzyme bound and in thepresence of a sufficient concentration (>10×Ki) of a potent inhibitorthe anisotropy of the unbound fluorescent ligand is measurably differentfrom the bound value.

The concentration of kinase enzyme should preferably be 2×Kf. Theconcentration of fluorescent ligand required will depend on theinstrumentation used, and the fluorescent and physicochemicalproperties. The concentration used must be lower than the concentrationof kinase enzyme, and preferably less than half the kinase enzymeconcentration.

The fluorescent ligand is the following compound:

which is derived from5-[2-(4-aminomethylphenyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-2-chlorophenoland rhodamine green.

Recombinant human p38α was expressed as a GST-tagged protein. Toactivate this protein, 3.5 μM unactivated p38α was incubated in 50 mMTris-HCl pH 7.5, 0.1 mM EGTA, 0.1% 2-mercaptoethanol, 0.1 mM sodiumvanadate, 10 mM MgAc, 0.1 mM ATP with 200 nM MBP-MKK6 DD at 30 degreesfor 30 mins. Following activation p38α was re-purified and the activityassessed using a standard filter-binding assay.

-   Protocol: All components are dissolved in buffer of composition 62.5    mM HEPES, pH 7.5, 1.25 mM CHAPS, 1 mM DTT, 12.5 mM MgCl₂ with final    concentrations of 12 nM p38α and 5 nM fluorescent ligand. 30 μl of    this reaction mixture is added to wells containing 0.1 μl of various    concentrations of test compound (0.02 nM-25 μM final) or DMSO    vehicle (1.7% final) in Greiner low volume 384 well black microtitre    plate and equilibrated for 30-60 mins at room temperature.    Fluorescence anisotropy is read in Molecular Devices Acquest    (excitation 485 nm/emission 535 nm).-   Definitions: Ki=dissociation constant for inhibitor binding    -   Kf=dissociation constant for fluorescent ligand binding

It is noted that there are two assay formats shown above for theFluorescence anisotropy kinase binding assay. The only differencebetween these two assays is the volume used and the plate type. It hasbeen demonstrated that there is no difference in potency between the twoformats, and that the assays are considered to be equivalent. Theresults described herein may have been performed in either assay formatand are not differentiated as to which.

Results

Compounds are considered active in this assay if they demonstrate apIC50 of greater than 4.6 up to about a pIC50 of 9.0.

Representative compounds of Formula (I) and (Ia) as described in theExamples 1(d), 1(g), 2(b), 3(b), 4(c), 5, 6(b), 7(c), 7(d), 8(c), 10(b),(c) and (e), 11 to 14, 15(a), (b), and (c), 16 to 18, 19(b), 20, 21(a)and (b), 22, 23(c), (d), and (e), 24 to 26, 27(b), 28, 29(c), 30(c),31(b), 32, 33(b), 34(d), 35 to 37, 38(b), 39 to 55, 57 to 60, 62 to 83,85, 86(c), 87(b), 88(c), 89 to 95, 96(b), 117, 118(c), 119 to 140, 142to 148, 149(a) and (c), 150 to 152, 154, 155, 156(a), (b) and (c), 157to 159, 161, 163(a), (b) and (c), 164 to 226 are active in this assay.

Compounds of Examples 19(a), 97, 98, 100 to 103, 104(c), 105 to 108,110, 153, 160 demonstrated an apparent pIC50 of less than 4.8 in thisassay.

The compound of Example 84 upon multiple runs provided a broad range ofdata, ranging from 5.3 to less than 5.75 of a pIC50 in this assay.Compounds of Examples 99, 141, and 162 upon multiple runs provided abroad range of data, ranging from 5.9 to less than 4.8 of a pIC50 inthis assay.

TR-FRET Assay Time-Resolved Fluorescence Resonance Energy TransferKinase Standard Assay

Recombinant human p38α was expressed as a His-tagged protein. Toactivate this protein, 3 μM unactivated p38α was incubated in 200 mMHepes pH 7.4, 625 mM NaCl, 1 mM DTT with 27 nM active MKK6 (Upstate), 1mM ATP and 10 mM MgCl₂ The activity of the MKK6-activated p38α wasassessed using a time-resolved fluorescence resonance energy transfer(TR-FRET) assay.

Biotinylated-GST-ATF2 (residues 19-96, 400 nM final), ATP (125M final)and MgCl₂ (5 mM final) in assay buffer (40 mM HEPES pH 7.4, 1 mM DTT)were added to wells containing 1 ul of various concentrations ofcompound or DMSO vehicle (3% final) in NUNC 384 well black plate. Thereaction was initiated by the addition of MKK6-activated p38 (100 pMfinal) to give a total volume of 30 ul. The reaction was incubated for120 minutes at room temperature, then terminated by the addition of 15ul of 100 mM EDTA pH 7.4. Detection reagent (15 μl) in buffer (100 mMHEPES pH 7.4, 150 mM NaCl, 0.1% w/v BSA, 1 mM DTT) containingantiphosphothreonine-ATF2-71 polyclonal antibody (Cell SignallingTechnology, Beverly Mass. USA) labelled with W-1024 europium chelate(Wallac OY, Turku, Finland), and APC-labelled streptavidin (Prozyme, SanLeandro, Calif. USA) was added and the reaction was further incubatedfor 60 minutes at room temperature. The degree of phosphorylation ofGST-ATF2 was measured using a Packard Discovery plate reader(Perkin-Elmer Life Sciences, Pangbourne, UK) as a ratio of specific 665nm energy transfer signal to reference europium 620 nm signal.

Time-Resolved Fluorescence Resonance Energy Transfer Kinase Low VolumeAssay

Recombinant human p38α was expressed as a His-tagged protein. Toactivate this protein, 3 μM unactivated p38α was incubated in 200 mMHepes pH7.4, 625 mM NaCl, 1 mM DTT with 27 nM active MKK6 (Upstate), 1mM ATP and 10 mM MgC1₂ The activity of the MKK6-activated p38α wasassessed using a time-resolved fluorescence resonance energy transfer(TR-FRET) assay.

Biotinylated-GST-ATF2 (residues 19-96, 400 nM final), ATP (125 μM final)and MgCl₂ (5 mM final) in assay buffer (40 mM HEPES pH 7.4, 1 mM DTT)were added to wells containing 0.1 μl of various concentrations ofcompound or DMSO vehicle (1.7% final) in Greiner low volume 384 wellblack plate. The reaction was initiated by the addition ofMKK6-activated p38α (100 μM final) to give a total volume of 6 μl. Thereaction was incubated for 120 minutes at room temperature, thenterminated by the addition of 3 μl of detection reagent in buffer (100mM HEPES pH 7.4, 150 mM NaCl, 0.1% w/v BSA, 1 mM DTT, 100 mM EDTA)containing antiphosphothreonine-ATF2-71 polyclonal antibody (CellSignalling Technology, Beverly Mass., USA) labelled with W-1024 europiumchelate (Wallac OY, Turku, Finland), and APC-labelled streptavidin(Prozyme, San Leandro, Calif., USA). The reaction was further incubatedfor 60 minutes at room temperature. The degree of phosphorylation ofGST-ATF2 was measured using a BMG Rubystar plate reader (BMG, UK) as aratio of specific 665 nm energy transfer signal to reference europium620 nm signal.

It is noted that there are two assay formats shown above for theTime-resolved fluorescence resonance energy transfer kinase assay. Theonly difference between these two assays is the volume used and theplate type. It has been demonstrated that there is no difference inpotency between the two formats, and that the assays are considered tobe equivalent. The results described herein may have been performed ineither assay format and are not differentiated as to which.

Results

Compounds would be considered active in this assay if they demonstrateda pIC50 of greater than 4.6 up to about a pIC50 of greater than 10.0.

Representative compounds of Formula (I) and (Ia) as described inExamples 1(d), 5, 7(c), 8c, 9, 11, 13, 15(c), 16, 17, 19(b), 20, 21(a),21(b), 22, 24, 26, 29(c), 30(c), 31(b), 32, 33(b), 34(d), 35 to 37,38(b), 39 to 55, 58, 59, 62 to 85, 86(c), 87(b), 88(c), 89 to 95, 96(b),98 to 101, 103, 106, 111(c), 112 to 116, 118(c), 119 to 140, 142 to 147,149(a), 149(c), 150 to 152, 156(a), (b) and (c), 157 to 226, 227(b),228(b), 229, 230(b) were tested in the above assay and found active.

Compounds of Examples 18 and 1(g) upon multiple runs provided a broadrange of data, ranging from 8.1 to less than 4.8 of a pIC50 in thisassay. Compounds of Examples 117, 108, 106, 104(c), 102, 97 uponmultiple runs provided a broad range of data, ranging from 6.8 to lessthan 5.8 of a pIC50 in this assay. Compounds of Examples 105, 107, and110 have demonstrated a pIC50 of <5.8 in this assay. The compound ofExample 27(b) demonstrated a pIC50 of <4.8 in this assay.

For purposes herein for the HTRF assay and the Fluorescence anisotropykinase binding assay:

pIC₅₀ IC₅₀ (nM) IC₅₀ (uM) 4.00 100,000.0 100 5.00 100,000.0 10 6.001,000.0 1 7.00 100.0 0.1 8.00 10.0 0.01 9.00 1.0 0.001 10.00 0.1 0.0001TNF-Stimulated IL-8 Production from Human Neutrophils

The effect of test compounds on TNF-stimulated IL8 production by humanneutrophils is measured as follows. Neutrophils are prepared from bloodobtained from consenting donors, using standard methods. Blood iscollected in heparinized syringes and layered over histopaque (30 ml/20ml). Following centrifugation, the red cell pellet is resuspended in PBSand purified over a dextran gradient. Red blood cells are lysed withwater for 40 sec, remaining granulocytes collected by centrifugation andresuspended at 1.5×10̂6 cells/ml. Cells are added (0.5-1 ml) to 48 wellplates already containing compound at 1000× final concentration in neatDMSO or 10% DMSO in RPMI1640 with 10% FBS. TNF (final concentration 100ng/ml) is used as the stimulus. Cells incubated for approximately 20 hrsat 37° C., 5% CO2. Levels of IL-8 in the cell free supernatant aredetermined by sandwich ELISA, and inhibition relative to a control withDMPO but no compound is calculated.

Results

Compounds would be considered active in this assay if they demonstratedan IC50 of less than 10 uM up to about an IC50 of less than 0.0001 uM,and were screened at concentrations up to 100 nM.

Representative compounds of Formula (I) and (Ia) as described inExamples 2(b), 3(b), 7(c) and (d), 8(c), 9, 11-14, 15(c), 16-18, 19(b),20, 21(b), 22, 23(c) and (e), 24, 26, 27(b), 28, 29(c), 30(c), 31(b),32, 33(b), 34(d), 35-37, 38(b), 39-48, 51-55, 58, 63-64, 70, 74-83, 85,86(c), 87(b), 88(c), 89, 91-95, 111(c), 114, 117, 120-122, 124, 127,130, 148, 151, 177-180, 182-189, 194, 196, 198, 200-201, 203-204,227(b), and 230(a) were tested in the above assay and found active.

Compounds of Examples 4(c), 5, 6(b), 15(b), 23(d), 49-50, 62, 65, 84,90, 96(b), 98-101, 103, 104(c), 105-110, 113, 116, 125, 146, 149(c),152-155, 156(a), 156(b), 156(c), 159, 160, 197, 228(b), 229, and 230(b)demonstrated an IC50 of greater than 0.1 uM in this assay. These latercompounds were screened at a different top concentration than the abovegrouping. While these compounds were not found to inhibit the productionof IL-8 at greater than 50% at a 100 nM, some of these would be expectedupon retesting with increasing concentrations to reach 50% inhibition.

Compounds of Examples 71 and 72 demonstrated an IC50 of greater than0.001 uM in this assay. These later compounds were screened at adifferent top concentration than the above grouping.

Compounds of Examples 1(g), 15(a), 19(a) upon multiple runs provided abroad range of data, ranging from an IC50 of 0.04 uM to an IC50 ofgreater than 0.1uM in this assay. Example 115 upon multiple runsprovided a broad range of data, ranging from an IC50 of less than 0.001uM to greater than 0.1 uM in this assay. While these compounds were notfound to inhibit the production of IL-8 at greater than 50% at a 100 nM,some of these would be expected upon retesting with increasingconcentrations to reach 50% inhibition.

Rat LPS Neutrophilia Model

The effect of compounds on the influx of neutrophils to the lung inLPS-challenged rats is evaluated as follows. The test compound issuspended in one of the following solutions: 0.5% tween 80/PBS, 0.5%tween 80/saline, 10% EtOH/saline (with pH adjusted to 2.0, or 8.0 withHCl, or unadjusted), Saline @ pH 2.0, 6.5 or 8.0, 0.5% Tragacanth, 1%DMSO/20% Encapsin/Saline, or acidified 5% Tragacanth. The suspensionprocess may be aided by the use of a glass homogenizer. Forintratracheal administration, the animals are anesthetized with inhaledisoflurane and placed in a supine position, the trachea is intubatedwith a steel gavage needle (1.5 inch, 22 gauge, small ball) or aPenn-Century Microsprayer Aerosolizer (model IA-1B) and 200 ul of dosingsolution is delivered. The animals are visually monitored during therecovery process, which typically occurs within two minutes.

Rats treated with compound or vehicle (15 min-24 hours pretreatment) areexposed to an LPS aerosol (100 ug/ml) for 15 min. Four hours later therats are euthanized with pentobarbital (100 mg/kg, i.p.) and the airwaysare lavaged with 5 washes of 5 ml of phosphate buffered saline. Theharvested cells are stained (Diffquick) and counted to determine totaland differential cell data. In a typical study, macrophages represent40-70% of the total cells, and polymorphonuclear cells 30-60% of thetotal cells Inhibition of neutrophil levels relative to no compoundcontrols is calculated based on the differential counts.

The assay has varying conditions, such as concentration, pretreat time,form of the compound (crystalline, amorphous, salts, micronised), and awet or dry application of the compound. The data is obtained as %inhibition using a particular concentration and pretreat time. While anumber of the compounds were found to be statistically nonsignificant(p>0.05), it is expected that upon retesting with either increasingconcentrations, and/or a change in pretreat time that some of them mayreach statistical significance (p<0.05).

Representative compounds of Formula (I) have been tested in this assay.

Compounds of Examples 8(c), 11, 29(c), 36, 40, 42, 70, 71, 72, 91, 92,112, 118(c), 119, 120, 127, 137, 138, 140, 144, and 200 were found tohave statistically significant inhibition of neutrophilia in at leastone of the range of conditions tested in this assay.

Compounds of Examples 9, 17, 23(e), 24, 28, 32, 34(d), 37, 39, 53, 57,60, 86(c), 87(b), 93, 124, 134, 148, 151, 166, 172, 176, and 179 werefound to have statistically nonsignificant inhibition of neutrophilia inat least one of the range of conditions tested in this assay.

Compounds of Examples 7(c), 23(c), 26, 43, 60, 174, and 175 were foundto be inactive in this assay.

TNF-α in Traumatic Brain Injury Assay

This assay provides for examination of the expression of tumor necrosisfactor mRNA in specific brain regions which follow experimentallyinduced lateral fluid-percussion traumatic brain injury (TBI) in rats.Since TNF-α is able to induce nerve growth factor (NGF) and stimulatethe release of other cytokines from activated astrocytes, thispost-traumatic alteration in gene expression of TNF-α plays an importantrole in both the acute and regenerative response to CNS trauma. Asuitable assay may be found in WO 97/35856 whose disclosure isincorporated herein by reference.

CNS Injury Model for IL-b mRNA

This assay characterizes the regional expression of interleukin-1β(IL-1β) mRNA in specific brain regions following experimental lateralfluid-percussion traumatic brain injury (TBI) in rats. Results fromthese assays indicate that following TBI, the temporal expression ofIL-1β mRNA is regionally stimulated in specific brain regions. Theseregional changes in cytokines, such as IL-1β play a role in thepost-traumatic pathologic or regenerative sequelae of brain injury. Asuitable assay may be found in WO 97/35856 whose disclosure isincorporated herein by reference.

Angiogenesis Assay:

Described in WO 97/32583, whose disclosure is incorporated herein byreference, is an assay for determination of inflammatory angiogenesiswhich may be used to show that cytokine inhibition will stop the tissuedestruction of excessive or inappropriate proliferation of bloodvessels.

Rhinovirus/Influenza Assay:

Cell lines, rhinovirus serotype 39, and influenza virus A/PR/8/34 werepurchased from American Type Culture Collection (ATCC). BEAS-2B cellswere cultured according to instructions provided by ATCC using BEGM(bronchial epithelial growth media) purchased from Clonetics Corp. HELAcell cultures, used for detection and titration of virus, weremaintained in Eagle's minimum essential media containing 10% fetal calfserum, 2 mM 1-glutamine, and 10 mM HEPES buffer (MEM).

A modification of the method reported by Subauste et al., Supra, for invitro infection of human bronchial epithelial cells with rhinovirus wasused in these studies. BEAS-2B cells (2×10⁵/well) were cultured incollagen-coated wells for 24 hours prior to infection with rhinovirus.Rhinovirus serotype 39 was added to cell cultures for one hourincubation at 34° C. after which inoculum was replaced with fresh mediaand cultures were incubated for an additional 72 hours at 34° C.Supernatants collected at 72 hours post-infection were assayed forcytokine protein concentration by ELISA using commercially availablekits (R&D Systems). Virus yield was also determined from culturesupernatants using a microtitration assay in HELA cell cultures(Subauste et al., supra 1995). In cultures treated with p38 kinaseinhibitors, drug was added 30 minutes prior to infection. Stocks ofcompounds were prepared in DMSO (10 mM drug) and stored at −20° C.

For detection of p38 kinase, cultures were incubated in basal mediawithout growth factors and additives to reduce endogenous levels ofactivated p38 kinase. Cells were harvested at various time points afteraddition of rhinovirus. Detection of tyrosine phosphorylated p38 kinaseby immunoblot was analyzed by a commercially available kit and wasperformed according to the manufacturer's instructions (PhosphoPlus p38MAPK Antibody Kit: New England BioLabs Inc.).

In some experiments, BEAS-2B cells were infected with influenza virus(strain A/PR/8/34) in place of rhinovirus. Culture supernatant washarvested 48 and 72 hour post-infection and tested by ELISA for cytokineas described above.

-   Cells and Virus: Influenza A/PR/8/34 sub type H1N1 (VR-95 American    Type Culture Collection, Rockville, Md.) was grown in the allantoic    cavity of 10 day old chicken eggs. Following incubation at 37° C.,    and refrigeration for 2½ hours at 4° C., allantoic fluid was    harvested, pooled, and centrifuged (1,000 rcf; 15 min; 4° C.) to    remove cells. Supernatent was aliquoted and stored at −70° C. The    titer of the stock culture of virus was 1.0×10¹⁰ Tissue Culture    Infective Dose/ml (TCID₅₀)-   Inoculation procedure: Four-six week old female Balb/cAnNcrlBr mice    were obtained from Charles River, Raleigh, N.C. Animals were    infected intranasally. Mice were anesthetized by intraperitioneal    injection of Ketamine (40 mg/kg; Fort Dodge Labs, Fort Dodge, Iowa)    and Xylazine (5 mg/kg; Miles, Shawnee Mission, Kans.) and then    inoculated with 100 TCID50 of PR8 diluted in PBS in 20 ul. Animals    were observed daily for signs of infection. All animal studies were    approved by SmithKline Beecham Pharmaceuticals Institutional Animal    Care and Use Committee.-   Virus titration: At various times post infection, animals were    sacrificed and lungs were aseptically harvested. Tissues were    homogenized, in vials containing 1 micron glass beads (Biospec    Products, Bartlesville, Okla.) and 1 ml. of Eagles minimal essential    medium. Cell debris was cleared by centrifugation at 1,000 rcf for    15 minutes at 4° C., and supernatants were serially diluted on    Madin-Darby canine kidney (MDCK) cells. After 5 days of incubation    at 37° C. (5% CO₂), 50 μl of 0.5% chick red blood cells were added    per well, and agglutination was read after 1 hour at room    temperature. The virus titer is expressed as 50% tissue culture    infective dose (TCID₅₀) calculated by logistic regression.-   ELISA: Cytokine levels were measured by quantitative ELISA using    commercially available kits. Ear samples were homogenized using a    tissue minser in PBS. Cell debris was cleared by centrifugation at    14,000 rpm for 5 minutes. The cytokine concentrations and thresholds    were determined as described by the manufacturer; IL-6, IFN-γ, and    KC (R&D Systems, Minneapolis, Minn.).-   Myeloperoxidase Assay: Myeloperoxidase (MPO) activity was determined    kinetically as described by Bradley et al. (1982). Briefly, rabbit    cornea were homogenized in Hexadecyl Trimethyl-Ammonium Bromide    (HTAB) (Sigma Chemical Co. St. Louis, Mo.) which was dissolved in    0.5 m Potassium phosphate buffer (J.T. Baker Scientific,    Phillipsburg, N.J.). Following homogenization, the samples were    subjected to freeze-thaw-sonication (Cole-Parmer 8853, Cole-Parmer,    Vernon Hills, Ill.) 3 times. Suspensions were then cleared by    centrifugation at 12,500×g for 15 minutes at 4° C. MPO enzymatic    activity was determined by colormetric change in absorbance during a    reaction of O-Dianisidine dihydrochloride (ODI) 0.175 mg/ml (Sigma    Chemical Co. St. Louis, Mo.) with 0.0002% Hydrogen peroxide (Sigma    Chemical Co. St. Louis, Mo.). Measurements were performed by using a    Beckman Du 640 Spectrophotometer (Fullerton, Calif.) fitted with a    temperature control device. 50 ul of material to be assayed was    added to 950 ul of ODI and change in absorbance was measured at a    wave length of 460 nm for 2 minutes at 25° C.-   Whole Body Plethysomography: Influenza virus infected mice were    placed into a whole body plethysomograph box with an internal volume    of approximately 350-ml. A bias airflow of one 1/min was applied to    the box and flow changes were measured and recorded with a Buxco XA    data acquisition and respiratory analysis system (Buxco Electronics,    Sharon, Conn.). Animals were allowed to acclimate to the    plethysmograph box for 2 min. before airflow data was recorded.    Airway measurements were calculated as Penh (enhanced pause). Penh    has previously been shown as an index of airway obstruction and    correlates with increased intrapleural pressure. The algorithm for    Penh calculation is as follows: Penh=[(expiratory time/relaxation    time)−1]×(peak expiratory flow/peak inspiratory flow) where    relaxation time is the amount of time required for 70% of the tidal    volume to be expired.-   Determination of arterial oxygen saturation. A Nonin veterinary hand    held pulse oximeter 8500V with lingual sensor (Nonin Medical, Inc.,    Plymouth Minn.) was used to determine daily arterial oxygen    saturation % SpO2 as described (Sidwell et al. 1992 Antimicrobial    Agents and Chemotherapy 36:473-476).

Additional data and assay modifications may be found in PCT/US00/25386,(WO 01/19322) filed 15 Sep. 2000, whose disclosure is incorporatedherein by reference in its entirety.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The above description fully discloses the invention including preferredembodiments thereof Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore, the Examples herein are tobe construed as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

1. The compound3-{8-(2,6-difluorophenyl)-2-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide,or pharmaceutically acceptable salt thereof.
 2. The compound accordingto Claim 1 wherein the pharmaceutically acceptable salt is selected fromthe group consisting of acetate, benzenesulfonate, benzoate,bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate,camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, ethanesulphonate, formate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydrogenphosphate, hydroiodide, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, monopotassium maleate,mucate, napsylate, nitrate, N-methylglucamine, oxalate, oxaloacetate,pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,piruvate, polygalacturonate, saccharate, salicylate, stearate,subacetate, succinate, sulphate, tannate, tartrate, teoclate, tosylate,triethiodide, trifluoroacetate and valerate.
 3. A pharmaceuticalcomposition comprising a compound according to claim 1, orpharmaceutically acceptable salt thereof in admixture with one or morepharmaceutically acceptable carriers, diluents or excipients.
 4. Apharmaceutical composition according to claim 3 adapted foradministration by intranasal or oral inhalation means.
 5. The compound3-{8-(2,6-difluorophenyl)-2-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide.
 6. A pharmaceutical composition comprising a compoundaccording to claim 5 in admixture with one or more pharmaceuticallyacceptable carriers, diluents or excipients.
 7. A pharmaceuticalcomposition according to claim 6 adapted for administration byintranasal or oral inhalation means.